Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women

Lorna Gibson; David Lawrence; Claire Dawson; Judith Bliss

doi:10.1002/14651858.CD003370.pub3

Inhibidores de la aromatasa para el tratamiento del cáncer de mama avanzado en mujeres posmenopáusicas

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CAAN. Ongoing study. February 2002. Contact author for more information.

ECOG E4101. Ongoing study. Starting date of trial not provided. Contact author for more information.

SofeaPhase III. Ongoing study. March 2004. Contact author for more information.

Phase III EORTC-10951. Ongoing study. Starting date of trial not provided. Contact author for more information.

Referencias adicionales

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Referencias de otras versiones publicadas de esta revisión

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Gibson LJ, Dawson CK, Lawrence DH, Bliss JM. Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women. Cochrane Database of Systematic Reviews 2007, Issue 1.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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Alonso‐Munoz 1988

*Study characteristics*
Methods	Spain, multicentre, N = 105, Dec 1982 ‐ Dec 1985 Three arm trial (only two arms included in review N = 70) Randomisation method not given Baseline characteristics balanced
Participants	Age range 37 ‐ 75y Proven metastatic breast cancer, measurable disease sites No previous endocrine therapy
Interventions	AG (500mg for 2w, then 100mg) versus TAM 40mg versus AG + TAM 40mg Numbers in each treatment arm: 35 versus 35 versus 35 (AG+TAM arm data excluded from review N = 35) Assessable patients (two included arms): 31 versus 34 Patients evaluable for toxicity (two included arms): 33 versus 34
Outcomes	Toxicity, TTP, response rate Not survival
Notes	11 not evaluable (4 AG, 6 TAM + AG, 1 TAM) due to: 4 died within 6w, 1 discontinued treatment, 5 toxicity, 1 lost to FU FU duration not given TTP not given by treatment arm
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Blinding (performance bias and detection bias) All outcomes	High risk

Bezwoda 1998

*Study characteristics*
Methods	South Africa, multicentre, N = 96 Double‐blind, double‐dummy Balanced block stratification by centre Baseline slight imbalance in ER status: 28% versus 20% ER+
Participants	Age range 44 ‐ 82y Measurable or evaluable metastatic breast cancer Prior TAM treatment No previous treatment with AI ECOG perf status < 3
Interventions	Fadrozole 2mg versus MA 160mg Numbers in each treatment arm: 46 versus 50 Assessable patients: 46 versus 50 Patients evaluable for toxicity: 46 versus 50 Treatment until progression or for 1y; median duration 20w
Outcomes	Primary ‐ response rate, TTP, TTF, survival Secondary ‐ QOL, performance status, pain assessment
Notes	FU to relapse or death Median FU not stated Intention‐to‐treat analysis Subsidiary analysis on a per protocol basis (41 versus 43) 7 major protocol violations, 2 refusals, 1 early death, 1 lost to FU (numbers not consistent)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	balanced block stratification by centre
Allocation concealment (selection bias)	Low risk	adequate
Blinding (performance bias and detection bias) All outcomes	Low risk	double‐blind, double‐dummy

Bonneterre 2001

*Study characteristics*
Methods	International, multicentre trial, combined results of two trials Feb 1996 ‐ July 1998 97 sites in US and Canada, N = 353 83 sites in Europe, Australia, New Zealand, South Africa, South Amercia, N = 668 Total randomised = 1021 Double‐blind, double‐dummy Baseline characteristics well‐balanced
Participants	Age range 30 ‐ 92y Advanced or metastatic breast cancer
Interventions	Anastrozole 1mg versus TAM 20mg Numbers in each treatment arm: 171 versus 182 (N America) and 340 versus 328 (rest of world) Assessable patients: 511 versus 510 Patients evaluable for toxicity: 506 versus 511 Treatment continued until disease progression
Outcomes	Primary ‐ objective response, TTP, tolerability Secondary ‐ TTF, survival
Notes	FU to progression and death Median FU not known Number of dropouts not given
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	adequate
Blinding (performance bias and detection bias) All outcomes	Low risk	double‐blind, double‐dummy

Buzdar 1996a

*Study characteristics*
Methods	International, multicentre. 122 centres: 49 in North America, 73 in Europe, Australia, South Africa, Double‐blind anastrozole, open megestrol acetate Randomisation method ‐ blocks of 6 (Europe), blocks of 3 (N America), parallel groups Two trials combined (N = 764): North America (N = 346) and Europe, Australia, South Africa (N = 378) Three‐arm trial (only two arms included in review N = 516) Baseline: apparent imbalance in one treatment group (believed to be artefact)
Participants	Age range 29 ‐ 97y Advanced breast cancer Progressed on anti‐oestrogen for advanced disease or progressed on or during adjuvant TAM WHO perf status < 3
Interventions	anastrozole 1mg versus anastrozole 10mg versus MA 160mg Numbers in each treatment arm: 263 versus 248 versus 253 (anastrozole 10mg arm excluded from review N = 248) Assessable patients (two included arms): 263 versus 253 Patients evaluable for toxicity (two included arms): 262 versus 253 Treatment continued until disease progression or withdrawal from treatment for other reasons
Outcomes	Primary ‐ TTP, tumour response, tolerability Secondary ‐ TTF, response duration, survival Clinical assessment every 4w until week 24, every 12w until week 48, then every 3m until progression
Notes	FU median duration 6m 3 no treatment, 1 wrong treatment, 8 lost to FU Intention‐to‐treat analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	blocks of 6 (Europe), blocks of 3 (N America), parallel groups
Allocation concealment (selection bias)	Low risk	adequate
Blinding (performance bias and detection bias) All outcomes	Low risk	double‐blind anastrozole, open megestrol acetate

Buzdar 1996b

*Study characteristics*
Methods	Protocol 03 Multicentre, 47 sites, N = 380 Feb 1989 ‐ Dec 1991 Double‐blind, parallel, controlled equivalence Randomisation method not specified
Participants	Age range 35 ‐ 92y Metastatic breast cancer At least one prior hormonal treatment for metastic disease more than 3m previously Prior AI use an exclusion Performance status < 3
Interventions	Fadrozole 2mg versus MA 160mg Numbers in each treatment arm: 196 versus 184 Drug code broken 18m after end of enrolment Assessable patients: 195 versus 184 Patients evaluable for toxicity: 196 versus 184 Treatment continued until disease progression
Outcomes	Objective response rate, TTP, survival, toxicity, duration of response, survival, QOL
Notes	Published together with protocol 06 (Buzdar 1996c) FU until progression Intention‐to‐treat analysis N = 379 1 patient excluded but included in safety and tolerability
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	randomisation method not specified
Allocation concealment (selection bias)	Low risk	adequate
Blinding (performance bias and detection bias) All outcomes	Low risk	double‐blind, parallel, controlled equivalence

Buzdar 1996c

*Study characteristics*
Methods	Protocol 06 Multicentre, 55 sites, N = 303 Oct 1989 ‐ Aug 1992 Double‐blind, parallel, controlled equivalence Randomisation method not specified
Participants	Age range 36 ‐ 92y Metastatic breast cancer At least one prior hormonal treatment for metastic disease more than 3m previously Prior AI use an exclusion Performance status<3
Interventions	Fadrozole 2mg versus MA 160mg Numbers in each treatment arm: 152 versus 151 Assessable patients: 150 versus 148 Patients evaluable for toxicity:152 versus 151 Drug code broken 18m after end of enrolment Treatment continued until disease progression
Outcomes	Primary ‐ overall tumour response (TTP, TTF, survival) Other ‐ earliest diagnosis of PD, tolerability, safety, QOL
Notes	Published together with protocol 03 (Buzdar 1996b) FU: 33m for tumour response/safety (median 5.5m) 45m for survival (median 18 to 20m) Intention‐to‐treat analysis N = 298 Not designed or powered to detect differences in survival
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	randomisation method not specified
Allocation concealment (selection bias)	Low risk	adequate
Blinding (performance bias and detection bias) All outcomes	Low risk	double‐blind, parallel, controlled equivalence

Buzdar 2001

*Study characteristics*
Methods	International, multicentre, 120 sites in US, Canada, Europe, N = 602 Three‐arm trial (only two arms included in review N = 400) Double‐blind, double dummy, phase III Randomisation by country w/o stratification by centre Enrolment over 30 months Baseline characteristics no imbalance
Participants	Age range not given Locally advanced/locoregionally recurrent/metastatic breast cancer At least one measurable/assessable lesion Relapsed or progressed while on anti‐oestrogen or relapsed within 12m of stopping antioestrogen Chemotherapy for advanced disease allowed KPF >=50%
Interventions	Letrozole 2mg versus letrozole 10mg versus MA 160mg Numbers in each treatment arm: 202 versus 199 versus 201 (letrozole 2mg arm excluded from review N = 202) Assessable patients: 182 versus 180 Patients evaluable for toxicity: 199 versus 201 Treatment continued until disease progression or withdrawal for other reason
Outcomes	Primary ‐ tumour response Secondary ‐ TTF, TTP, survival, QOL
Notes	FU period 48m after the first visit of the last patient randomised Intention‐to‐treat analysis 23 ineligible and excluded from tumour analyses
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	randomisation by country w/o stratification by centre
Allocation concealment (selection bias)	Low risk	adequate
Blinding (performance bias and detection bias) All outcomes	Low risk	double‐blind, double‐dummy

Canney 1988

*Study characteristics*
Methods	UK, number of centres not given, N = 218 Randomised without stratification, performed centrally by phone over 24m
Participants	Median age 64y Actively progressive disease Received hormonal therapy with tamoxifen Received no anticancer therapy within preceding 4w
Interventions	AG (250mg for 2w, increased to 500mg if not toxic effect plus 40mg HC) versus high dose MPA 1000mg Numbers in each treatment arm: 106 versus 112 Patients evaluable for toxicity: 106 versus 112
Outcomes	Duration of response, survival, time to response
Notes	FU duration: minumum 9m, median 55w for AG, 57w MPA 7 patients either violated protocol or did not meet entry criteria but included in analyses Crossover on failure No variation between groups in known prognostic variables
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	performed centrally by phone

Chia 2008

*Study characteristics*
Methods	International, multicentre, 138 centres, N = 693 Aug 2003 ‐ Nov 2005 Double‐blind, double‐dummy, phase III Trial acronym = EFECT Randomisation method not given Baseline characteristics well balanced except for ER+/PR+ ( 56.4% versus 67.5%)
Participants	Age range 32 ‐91y Locally advanced or metastatic disease Disease progression after prior non‐steroidal AI treatment At least one measurable or assessable lesion ER+/PR+ WHO perf status < 3
Interventions	Exemestane 25mg versus fulvestrant 500mg on day 0, 250mg on days 14 and 28, followed by 250mg every four weeks Numbers in each treatment arm: 342 versus 351 Assessable patients: 270 versus 270 Treatment continued until disease progression
Outcomes	Primary ‐ TTP Secondary ‐ objective response, CB, response duration, TTF, overall survival, tolerability, QOL
Notes	FU until death Intention‐to‐treat analysis 90% power to detect HR≥1.31
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Blinding (performance bias and detection bias) All outcomes	Low risk	double‐blind, double‐dummy

Dombernowsky 1998

*Study characteristics*
Methods	International, multicentre, Mar 1993 ‐ Sep 1994 10 countries, 91 sites, N = 551 Three‐arm trial (only two arms included in review N=363) Double‐blind, randomisation stratified by country; computer‐generated permuted blocks of size 6 or 3, 1:1:1 allocation Baseline characteristics balanced
Participants	Advanced/locoregionally recurrent/metastatic breast cancer Measurable/assessable disease Failure to respond to previous antioestrogen WHO perf status < 3
Interventions	Letrozole 0.5mg versus letrozole 2.5mg versus MA 160mg Numbers in each treatment arm: 188 versus 174 versus 189 (letrozole 0.5mg arm excluded from review N = 188) Assessable patients: 153 versus 166 Patients evaluable for toxicity: 174 versus 189
Outcomes	Primary ‐ overall tumour response (TTP, TTF, survival) Other ‐ earliest diagnosis of PD, tolerability, safety
Notes	FU: 33m for tumour response/safety (median 5.5m) 45m for survival (median 18 to 20m) Intention‐to‐treat analysis Not designed or powered to detect differences in survival as significant
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	stratified by country; computer‐generated permuted blocks of size 6 or 3, 1:1:1 allocation
Allocation concealment (selection bias)	Low risk	adequate
Blinding (performance bias and detection bias) All outcomes	Low risk	double‐blind

Falkson 1996

*Study characteristics*
Methods	South Africa, single centre, N = 80 Sep 1991 ‐ Dec 1994 Randomisation method not given Baseline: difference of 10y in median age of patients in arm 1 versus arm 2
Participants	Age range 43 ‐ 90y Progressive, inoperable, recurrent or metastatic breast cancer No prior treatment for advanced disease ECOG perf status < 3
Interventions	Fadrozole 2mg versus TAM 20mg Numbers in each treatment arm: 40 versus 40 Assessable patients: 36 versus 38 Patients evaluable for toxicity: 40 versus 40 Minimum treatment 8w
Outcomes	Survival, TTF, duration of overall response, toxicity, objective response rates
Notes	FU 14 to 1122d, median FU 153d Intention‐to‐treat analysis 2 ineligible, 1 lost to FU 74 patients evaluable

Freue 2000

*Study characteristics*
Methods	International, multicentre, 9 countries, 78 centres, N = 547 Aug 1991 ‐ Mar 1995 Computer‐generated random allocation w/o stratification Open study No difference in baseline characteristics
Participants	Age range not given Advanced disease Measurable disease ER/PR positive or unknown WHO perf status < 3 Only TAM as 1st line endocrine therapy
Interventions	Formestane 250mg im every 2w versus MA 160mg Numbers in each treatment arm: 276 versus 271 Assessable patients: 242 versus 237 Numbers for safety analysis: 276 versus 271 Treatment duration 12m
Outcomes	TTF, TTP, overall survival, overall response
Notes	FU until death Median FU not given 90% power to detect 33% difference in median TTF Intention‐to‐treat analysis Ineligible/non‐evaluable: 34 versus 34 Non‐cancer deaths: 2 versus 4 Discontinued for AE: 3 versus 13
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	computer‐generated random allocation without stratification
Allocation concealment (selection bias)	Low risk	adequate
Blinding (performance bias and detection bias) All outcomes	High risk	open

Gale 1994

*Study characteristics*
Methods	ECOG trial, multicentre, US, N = 249 1977 ‐ 1983 Stratified randomly permuted blocks of four Baseline characteristics relatively evenly balanced One institution had 60% versus 4% response rates
Participants	Age range not given Progressive, recurrent, metastatic breast cancer Measurable disease ECOG perf status < 4 No previous treatment with AG or TAM
Interventions	AG 250mg qid versus TAM 20mg Numbers in each treatment arm: 122 versus 119 Assessable patients: 108 versus 108
Outcomes	Tumour response, TTF, overall survival
Notes	Initial trial design changed in May 1979 (adrenalectomy treatment arm discontinued) Crossover on progression Crossover results not included Intention‐to‐treat analysis Adrenalectomy patients (N = 8) were excluded
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	stratified randomly permuted blocks of four
Allocation concealment (selection bias)	Low risk	adequate

Garcia‐Giralt 1992

*Study characteristics*
Methods	France, multicentre, N = 257 No randomisation details
Participants	Age range 36 ‐ 91y Histologically confirmed metastatic breast cancer ER+/PR+ Initial response to TAM before relapse
Interventions	AG 500mg + HC versus MPA 1000mg Numbers in each treatment arm: 131 versus 119 Assessable patients: 124 versus 112 Second‐line therapy after TAM
Outcomes	Tumour response, TTP, new metastases, AEs
Notes	Median FU not known Treatment until progression Crossover on progression 6 lost to FU, 1 man
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	not used

Gershanovich 1998

*Study characteristics*
Methods	International, multicentre, 11 countries, 86 sites N = 555 Three‐arm trial (only two arms included in review N = 363) Open‐label 1:1:1 Baseline no major differences
Participants	Median age letrozole 2.5mg 66y, letrozole 0.5 mg 64y, AG 65y Advanced or metastatic breast cancer Measurable/evaluable advanced disease WHO perf status < 3
Interventions	Letrozole 2.5mg versus letrozole 0.5mg versus AG 500 mg Numbers in each treatment arm: 185 versus 192 versus 178 (letrozole 2.5mg arm excluded from review N = 192) Assessable patients: 173 versus 162
Outcomes	Response, TTP, TTF, survival, tolerability and safety, overall survival
Notes	FU duration median > 20m 44 not assessable, counted as non‐responders in the analysis Median duration of treatment 5m Modified intention‐to‐treat population ie enrolled and received trial medication
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Blinding (performance bias and detection bias) All outcomes	High risk

Goss 1999

*Study characteristics*
Methods	Nov 1991 ‐ Dec 1995 Multicentre, 29 sites in Canada and 38 in US, N = 452 Open‐label, stratified by disease status Baseline characteristics comparable
Participants	Age range 39 ‐ 90y Advanced breast cancer, histologically confirmed Progressed after tamoxifen treatment
Interventions	Vorozole 2.5mg versus MA 160mg Numbers in each treatment arm: 225 versus 227 Assessable patients: 190 versus 185 Patients evaluable for toxicity: 195 versus 198 2nd line treatment after tamoxifen
Outcomes	Primary ‐ response rate Secondary ‐ TTP, survival, duration of response, safety subjective symptoms, QOL
Notes	Median FU 11.6m (vorozole), 9.9m (MA) 1 withdrawn before treatment 4 ineligible, 18 adverse events, 1 lost to FU, 18 other
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	stratified by disease status
Allocation concealment (selection bias)	Low risk	adequate
Blinding (performance bias and detection bias) All outcomes	High risk	open‐label

Goss 2007

*Study characteristics*
Methods	Multinational, multicentre, 60 centres in US, Canada, Russia, Ukraine, N = 865 Randomised, double‐blind, active control, phase III Randomisation in blocks of four, stratified by centre. Performed centrally, site notified by fax Treatment code unblinded after database lock Baseline characteristics well balanced
Participants	Median age letrozole 63y atamestane 65y Locally recurrent/advanced/ metastatic disease Measurable disease No AI or antioestrogen/SERM treatment in previous 12m ECOG perf status < 3
Interventions	Letrozole 2.5mg versus atamestane 500mg + toremifene 60mg Numbers in each treatment arm: 431 versus 434 Assessable patients: 297 versus 298
Outcomes	Primary ‐ TTP Secondary ‐ overall survival, TTF, tumour response, toxicity
Notes	FU to death Intention‐to‐treat analysis Treatment continued until disease progression or withdrawal for other reasons 80% power to detect a 24% increase in TTP
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	blocks of four, stratified by centre
Allocation concealment (selection bias)	Low risk	performed centrally, site notified by fax
Blinding (performance bias and detection bias) All outcomes	Low risk	double‐blind

Ingle 1986

*Study characteristics*
Methods	US, number of centres not known, N = 102 Randomised using Pocock‐Simon approach to adaptive randomisation, stratified
Participants	Age range 38 ‐ 83y Progressive metastatic disease Measurable or evaluable lesion ECOG perf status < 4 No prior therapy with either AG or TAM
Interventions	TAM 20mg versus TAM (20mg) + AG (500mg for 2 weeks then 1000mg) + HC (100mg daily for 2 weeks then 40mg) Numbers in each treatment arm: 49 versus 51 Assessable patients:49 versus 51 Patients evaluable for toxicity: 48 versus 46
Outcomes	Objective response, TTP, survival, toxicity
Notes	No data on duration of FU Target accrual = 160 but terminated early due to excess toxicity on the TAM + AG + HC arm 2 patients ineligible
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	used Pocock‐Simon approach to adaptive randomisation, stratified

Kaufmann 2000

*Study characteristics*
Methods	International, multicentre, Oct 1995 ‐ May 1998 19 countries, 144 centres N = 769 Double‐blind, parallel‐group, phase III Baseline characteristics comparable
Participants	Age range 30 ‐ 91y Advanced breast cancer Progressed or relapsed during tamoxifen treatment
Interventions	Exemestane 25mg versus MA 160mg Numbers in each treatment arm: 366 versus 403 Assessable patients: 337 versus 366 Patients evaluable for toxicity: 358 versus 400
Outcomes	Objective response, TTP, TTF, survival, tumour response, duration of tumour control, tumour related signs and symptoms, QOL, tolerability
Notes	FU median duration 48.9w 6 randomised but not treated 66 not evaluable for tumour response Intention‐to‐treat analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	adequate
Blinding (performance bias and detection bias) All outcomes	Low risk	double‐blind

Kleeberg 1997

*Study characteristics*
Methods	International, multicentre, 27 Jun ‐ 1 Dec 1995 18 centres, Europe and South Africa, N = 60 open‐label, parallel‐group, comparative Baseline good balance re age, weight, prior tamoxifen treatment
Participants	Age range 40 ‐ 84y Advanced breast cancer Measurable or evaluable disease
Interventions	Anastrozole 1mg oral per day versus formestane 250mg im every 2w Numbers in each treatment arm: 29 versus 31 Assessable patients: 29 versus 31 Treatment until disease progression
Outcomes	Primary ‐ oestradiol suppression and tolerability Secondary ‐ response rates, TTP, adverse events, blood oestrone sulphate, patient and doctor perception of treatment
Notes	No details re randomisation exclusions or FU Not powered to detect clinically significant difference in oestrogen suppression between the two arms
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Blinding (performance bias and detection bias) All outcomes	High risk	open‐label

Leitzel 1995

*Study characteristics*
Methods	Location and date of trial not given Multicentre, N = 300 Double‐blind, double‐dummy, parallel Randomisation method not given
Participants	Age range 18 ‐ 85y Metastatic breast cancer ECOG < 3
Interventions	Fadrozole 2mg versus MA 160mg Numbers in each treatment arm not given Duration of intervention not given Second‐line treatment
Outcomes	Tumour response, progression, c‐erbB‐2 antigen in serum
Notes	FU until death Results not given by treatment group Survival was not given by treatment group although it was measured
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	adequate
Blinding (performance bias and detection bias) All outcomes	Low risk	double‐blind, double‐dummy

Lundgren 1989

*Study characteristics*
Methods	Norway, multicentre, N = 176 Randomisation without stratification, details not given Baseline characteristics well balanced for most important prognostic variables, except main metastatic site
Participants	Mean age 62.0y versus 62.7y Advanced breast cancer Evaluable disease Previous treatment with TAM KPS >50
Interventions	AG 250mg bid for 2w then 250mg qid versus MA 160mg Numbers in each treatment arm: 86 versus 90 Assessable patients: 76 versus 74 Second‐line treatment
Outcomes	Response rate, reponse duration, survival, toxicity
Notes	Intention‐to‐treat analysis Excluded patients: 10 protocol violations/patient refusal; 12 early deaths; 4 adverse events
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	randomisation without stratification, details not given
Allocation concealment (selection bias)	Unclear risk	not used

Mauriac 2003

*Study characteristics*
Methods	Data were combined and published from two trials 0020 and 0021 (May 1997 ‐ September 1999) Trial 0020: multicentre, phase III, open, parallel group Europe, Australia and South Africa, 83 centres, N = 451 Trial 0021: multicentre, phase III, double‐blind, double‐dummy, parallel group North America, N = 400 Combined data from both trials included in review N = 851
Participants	Age range 33 ‐ 89y Locally advanced or metastatic breast cancer Progressed during adjuvant endocrine therapy or first‐line therapy for advanced disease WHO performance status < 3
Interventions	Anastrozole 1mg versus fulvestrant 250mg/month im Trial 0020: numbers in each treatment arm: 222 versus 229 Trial 0021: numbers in each treatment arm: 206 versus 194 Combined trials (included in review): numbers in each treatment arm: 423 versus 428 Assessable patients: 423 versus 428 Patients evaluable for toxicity: 423 versus 423 Continued until objective disease progression or other events required withdrawal
Outcomes	TTP, objective response, tolerability, QOL
Notes	Median FU 15.1m (combined data) Intention‐to‐treat analysis Additional to protocol: non‐inferiority of fulvestrant with anastrozole was carried out retrospectively
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	adequate
Blinding (performance bias and detection bias) All outcomes	Low risk	Trial 0020 open Trial 0021 double‐blind

Mercer 1993

*Study characteristics*
Methods	UK, query single‐centre, Jan 1987 ‐ Dec 1990, N = 61 No information regarding randomisation Groups well matched but after exclusions numbers small
Participants	Eligibility >50y Age range 45 ‐ 86y Advanced breast cancer Progressive disease on tamoxifen (adjuvant or treatment)
Interventions	Low dose AG 125mg versus HC 20mg Number in each treatment arm: 28 versus 33 Assessable patients: 27 versus 29
Outcomes	Tumour response, TTF, side‐effects, overall survival
Notes	FU details not given 5 patients excluded

Milla‐Santos 2003

*Study characteristics*
Methods	Spain, single‐centre, N = 238, May 1997 ‐ Dec 1999 Randomisation following Meinert's methodology. Baseline characteristics comparable
Participants	Age range 55 ‐ 77y Histologically confirmed advanced breast cancer, measurable disease sites No previous endocrine therapy ECOG<3
Interventions	Anastrozole 1mg versus TAM 40mg Numbers in each treatment arm: 121 versus 117 Assessable patients: 121 versus 117
Outcomes	Primary ‐ response rates, clinical benefit, TTP in patients achieving a CB, overall survival, toxicity
Notes	FU to 35m intention‐to‐treat analysis All patients evaluable Analysis cutoff 1 April 2001
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	randomisation following Meinert's methodology

Mourisden 2001

*Study characteristics*
Methods	International, multicentre, Nov 1996 ‐ Jan 1999 29 countries, 201 sites, N = 939 Double‐blind, double‐dummy, parallel group Baseline characteristics well balanced
Participants	Age range 31 ‐ 96y Locally advanced/locoregionally recurrent/metastatic breast cancer which is measurable/assessable Previous chemotherapy allowed for advanced disease WHO perf status < 3
Interventions	Letrozole 2.5mg versus TAM 20mg Numbers in each treatment arm: 453 versus 454 Assessable patients: 421 versus 423 Patients evaluable for toxicity: 455 versus 455 Treatment continued until disease progression
Outcomes	Primary ‐ TTP Secondary ‐ tumour response rate, TTF, ORR, survival, tolerability, KPS
Notes	FU median 32m Intention‐to‐treat analysis 907 analysed, 32 excluded Analysis cutoff March 2000 Survival not reported 729 discontinued treatment of which 391 'crossed over'
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	adequate
Blinding (performance bias and detection bias) All outcomes	Low risk	double‐blind, double‐dummy

Paridaens 2003

*Study characteristics*
Methods	International, multicentre, October 96 ‐ May 99 13 centres in 6 countries, N = 122 Open‐label phase II, randomised centrally using minimisation by EORTC, stratified by centre, adjuvant TAM, CT for metastatic disease, dominant disease site The trial was designed as a randomised phase II trial not to enable comparison of the efficacy of the two drugs but to establish a 'go, no‐go' rule for exemestane activity and safety before a formal randomised phase III trial. Patients randomised into the phase II trial will be incorporated into the phase III trial
Participants	Age range 37 ‐ 87y Measurable metastatic or locally recurrent inoperable breast cancer No prior hormone therapy for metastatic disease ECOG perf status < 3
Interventions	Exemestane 25mg versus TAM 20mg Numbers in each treatment arm: 62 versus 60 Intention‐to‐treat analysis: 61 versus 59 Toxicity data: 62 versus 59 Assessable patients: 56 versus 57 Patients evaluable for toxicity: 62 versus 59 Treatment continued until disease progression
Outcomes	Response rates Stop‐go for phase III Phase II therefore inadequate power, no statistical comparison of efficacy of endpoints between the two treatments were planned or performed
Notes	FU details 2 patients (1 exemestane, 1 TAM) ineligible as not having metastatic breast cancer, 7 additional (5 exemestane, 2 TAM) not evaluable for response, 1 lost to FU Phase II patients to be included in phase III trial Intention‐to‐treat analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	stratified by centre, randomised centrally by EORTC using minimisation
Allocation concealment (selection bias)	Low risk	adequate
Blinding (performance bias and detection bias) All outcomes	High risk	open‐label

Perez Carrion 1994

*Study characteristics*
Methods	International, multicentre, May 1988 ‐ December 1990, N = 409 Open study, equivalence trial Baseline characteristics well matched
Participants	Age range 38 ‐ 87y WHO perf status < 3
Interventions	Formestane 250mg im versus TAM 30mg Numbers in each treatment arm: 203 versus 206 Assessable patients: 173 versus 175
Outcomes	Response, survival, TTP, TTF, tolerability
Notes	FU details not reported 61 patients not evaluable, 10 lost to FU, 3 refusals Intention‐to‐treat analysis Trial closed early due to changes in clinical practice, ie increasing use of TAM in the adjuvant setting
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Blinding (performance bias and detection bias) All outcomes	High risk	open

Powles 1984

*Study characteristics*
Methods	Sept 1979 ‐ June 1983 UK, single‐centre, N = 222 Previously determined allocation list unknown to clinician. Baseline characteristics mean age marginally greater for TAM patients
Participants	Patients with disseminated breast cancer who had not previously received TAM, AG, or danazol No endocrine or chemotherapy within 6w
Interventions	TAM 20mg versus TAM 20mg + AG 750mg + danazol 300mg + HC 40mg Number on each treatment arm: 111 versus 111 Assessable patients: 99 versus 99 Patients evaluable for toxicity: 111 versus 111 Treatment continued until 3m assessment (unless rapid development of tumour in meantime) otherwise stopped when evidence of tumour progression arose either through failure to respond or because of relapse after response or stabilisation of disease
Outcomes	Tumour response
Notes	FU duration not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	previously determined allocation list unknown to clinician

Rose 1986

*Study characteristics*
Methods	Denmark, multicentre, June 1979 ‐ Sept 1988, 4 centres N = 313 Three‐arm trial (only two arms included in review N = 215) Randomised by centre, non‐stratified, stochastic array of numbers, closed envelope system Baseline characteristics well balanced
Participants	Age > 65y, age range 66 ‐ 84y First recurrence of metastatic breast cancer Progressive disease with measurable and/or evaluable lesions Performance status < 4
Interventions	TAM 30mg versus TAM 30mg + AG 250mg qid + HC 60mg v TAM 30mg + fluoxymesterone 20mg Numbers in each treatment arm: 108 versus 107 versus 98 (TAM + fluoxymesterone excluded from review N = 98) Assessable patients: 83 versus 94 Patients evaluable for toxicity: 87 versus 97 Treatment until progression (minimum 12 weeks)
Outcomes	TTF, TTP, survival, toxicity
Notes	FU duration not reported 34 ineligible 21 not evaluable 9 lost to FU 258 fully evaluable
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	randomised by centre, non‐stratified, stochastic array of numbers
Allocation concealment (selection bias)	Low risk	closed envelope system

Rose 2003

*Study characteristics*
Methods	International phase IIIb/IV, 19 countries, multicentre, 112 sites, N = 713 Dec 1997 ‐ Nov 1999 Open, random assignation stratified by centre via predetermined randomisation list Baseline characteristics well balanced
Participants	Age range 27 ‐ 92y Advanced or metastatic breast cancer with measurable and/or evaluable disease Histologically/cytologically confirmed Previous treatment with antioestrogen WHO performance status 0‐2
Interventions	Letrozole 2.5mg versus anastrozole 1mg Numbers in each treatment arm: 356 versus 357 Assessable patients: 299 versus 304
Outcomes	Primary ‐ TTP Secondary‐ objective response, duration of response, rate and duration of overall clinical benefit, overall survival, general safety
Notes	FU duration not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	random assignation stratified by centre
Allocation concealment (selection bias)	Low risk	predetermined randomisation list
Blinding (performance bias and detection bias) All outcomes	High risk	open‐label

Russell 1997

*Study characteristics*
Methods	May 1984 ‐ November 1990, Phase III, N = 288 Three‐arm trial (only two arms included in review N = 155) No stratification Treatment arms reasonably well balanced
Participants	Age range 33 ‐ 92y Progressive metastatic disease Measurable or evaluable lesion Patients had received TAM in advanced setting No prior MA or AG
Interventions	MA 160mg versus AG (500mg for 2w then 1000mg) + HC (100mg for 2w then 40mg) versus MA 160mg + AG (500mg for 2w then 1000mg) + hydrocortisone Numbers in each treatment arm: 75 versus 80 versus 80 (MA 160mg + AG (500mg for 2w then 1000mg) + hydrocortisone arm data excluded from review N = 80) Assessable patients: 42 versus 32 Patients evaluable for toxicity: 88 versus 89
Outcomes	Response, TTF, survival, toxicity
Notes	FU median duration amongst those still alive = 5.2y (213 had died) 53 ineligible (38 re misunderstanding re prior TAM use,7 due to life threatening visceral involvement, 3 with less than 6 months of TAM, 2 ER ‐, 1 prior hormonal therapy other than TAM, 1 no confirmed disease sites) Patients on MA or AG alone were crossed over after progression
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	no stratification

Samonis 1994

*Study characteristics*
Methods	Greece, single‐centre, N = 85 trial duration 2.5y Three‐arm trial (only two arms included in the review N = 57) Stratified randomisation ‐ statified into four groups by previous adjuvant treatment Table of baseline characteristics
Participants	Age range 50 ‐ 73y Metastatic breast cancer Measurable disease No previous treatment with AG or MPA KPS > 70%
Interventions	AG (250mg for 3d, then to 1000mg) versus MPA (500mg for 1m then twice weekly) versus AG + MPA Numbers in each treatment arm:28 versus 29 versus 28 (AG + MPA data excluded from review) Assessable patients (two included arms): 26 versus 27
Outcomes	Response to treatment, toxicity
Notes	FU duration not given Excluded patients: 1 accidental death, 4 lost to FU
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	statified into four groups by previous adjuvant treatment

Schmid 2001

*Study characteristics*
Methods	International, multicentre, N = 171 Three‐arm trial (only two arms included in review N = 112) Double‐blind
Participants	Mean age 64.5 Advanced breast cancer with bone metastases
Interventions	Letrozole 2.5mg versus letrozole 0.5mg versus MA 160mg Number in each treatment arm: 52 versus 59 versus 60 (letrozole 0.5mg arm excluded from review N = 59) Assessable patients: 48 versus 53
Outcomes	Objective response, clinical benefit, TTP, survival
Notes	Publication only available as abstract but sufficient data to include
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Blinding (performance bias and detection bias) All outcomes	Low risk	double‐blind

Thuerlimann 1996

*Study characteristics*
Methods	Switzerland, Phase III multicentre, 7 sites, N = 221 June 1988 ‐ Dec 1994 Phone randomisation, stratified, minimisation not double blind Baseline: prognostic factors well balanced apart from metastatic site
Participants	Age range 39 ‐ 87y Measurable/evaluable advanced breast cancer Indication for hormone treatment ECOG < 2
Interventions	Fadrozole 2mg versus TAM 20mg Numbers in each treatment arm: 111 versus 110 Eligible patients: 105 versus 107 Assessable patients: 103 versus 106 Patients evaluable for toxicity: 104 versus 107 First‐line treatment Treatment until progression
Outcomes	TTF, response rate, toxicity, overall survival, TTP, subjective benefit (not reported), duration of response
Notes	FU 7½ y Eligible patients: 212 9 ineligible(6 fadrozole, 3 TAM) 12 withdrawals Crossover only after failure so not analysed Analysis on data to Dec 1995, median FU of survivors 3y
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	minimisation, stratified
Allocation concealment (selection bias)	Low risk	phone randomisation
Blinding (performance bias and detection bias) All outcomes	Unclear risk	not double blind

Thuerlimann 1997

*Study characteristics*
Methods	Feb 1991 ‐ Jun 1995, N = 179 Stratified, central randomisation Baseline characteristics well balanced (only difference in weight)
Participants	Age range 43 ‐ 87y Advanced breast cancer Histologically and/or cytologically proven with measurable/evaluable disease Failed prior adjuvant and/or palliative tamoxifen treatment ie second‐line treatment Prior chemotherapy allowed ECOG perf status < 3
Interventions	Formestane 250mg im (biweekly) versus MA 160mg Numbers in each treatment arm: 91 versus 86 Assessable patients: 90 versus 83 Patients evaluable for toxicity: 90 versus 81
Outcomes	TTF, toxicity
Notes	FU duration not reported 2 ineligible, 4 dropouts 173 fully evaluable After failure of randomised treatment 75 patients 'crossed over'
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	stratified
Allocation concealment (selection bias)	Low risk	central randomisation

Tominaga 2003

*Study characteristics*
Methods	Japan, multicentre, 62 sites, N = 157 Double‐blind, double‐dummy, parallel groups Adaptive dynamic balancing method
Participants	Mean age 59.7y (letrozole) and 61.0y (fadrozole) Advanced disease Measurable or assessable pathological lesions
Interventions	Letrozole 1mg versus fadrozole 2mg Numbers in each treatment arm: 79 versus 78 Assessable patients: 77 versus 77 Minimum 8w treatment Treatment until disease progressed or patient experienced toxicity resulting in discontinuation
Outcomes	ORR, safety of letrozole compared to fadrozole
Notes	FU median 13.3m
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	adaptive dynamic balancing method
Allocation concealment (selection bias)	Low risk	adequate
Blinding (performance bias and detection bias) All outcomes	Low risk	double‐blind

KPS ‐ Karnofsky Performance Status
AG ‐ aminoglutethimide
AI ‐ aromatase inhibitor
CB ‐ clinical benefit
ECOG ‐ Eastern Cooperative Oncology Group
EORTC ‐ European Organization for the Research and Treatment of Cancer
ER ‐ oestrogen receptor
FU ‐ follow up
im ‐ intramuscular
mg ‐ milligram
TAM ‐ tamoxifen
MA ‐ megestrol acetate
MPA ‐ medroxy progesterone acetate
HC ‐ hydrocortisone
N ‐ number of patients
ORR ‐ objective response rate
PD ‐ progressive disease
perf status ‐ performance status
qid ‐ four times daily
QOL ‐ quality of life
TTF ‐ time to failure
TTP ‐ time to progression
d ‐ days
w ‐ weeks
m ‐ months
y ‐ years
WHO ‐ World Health Organisation
w/o ‐ without

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos
estudios en curso

Study	Reason for exclusion
Abe 2002	dose comparison of same AI (letrozole)
Bajetta 1994	dose comparison of same AI (formestane)
Bajetta 1997	dose comparison of same AI (exemestane)
Bajetta 1997a	dose comparison of same AI (letrozole)
Bajetta 1999	dose comparison of same AI (letrozole)
Beretta 1990	dose comparison of same AI (letrozole)
Bruning 1989	dose comparison of same AI (aminoglutethimide)
Bruning 1990	dose comparison of same AI (aminoglutethimide)
Castelazo 2004	non‐English (Spanish) paper
Cataliotti 2006	comparison of anastrozole versus tamoxifen as neoadjuvant treatment
Dixon 2000	dose‐comparison of same AI (anastrozole)
Dowsett 1989	dose‐comparison of same AI (formestane)
Dowsett 1990	dose‐comparison of same AI (fadrozole)
Dowsett 1994	dose‐comparison of same AI (fadrozole)
Dowsett 1995	dose‐comparison of same AI (letrozole)
Eiermann 2001	comparison of letrozole versus tamoxifen as pre‐operative treatment
Geisler 1996	outcome: aromatase levels and plasma oestrogen levels
Geisler 2002	outcome: aromatase levels and plasma oestrogen levels
Ingle 1997	dose comparison of same AI (letrozole)
Johnston 1994	dose comparison of same AI (vorozole)
Miller 1996b	dose comparison of same AI (fadrozole)
Pronzato 1993	AI (aminoglutethimide) versus same AI plus tamoxifen
Raats 1992	dose comparison of same AI (fadrozole)
Smith 2005	comparison of anastrozole versus tamoxifen as neoadjuvant treatment
Svenstrup 1994	dose comparison of same AI (fadrozole)
Wang 2003	non‐English (Chinese) paper

Characteristics of ongoing studies [ordered by study ID]

Ir a:

estudios incluidos
estudios excluidos

CAAN

Study name	CAAN
Methods
Participants	Target accrual = 90 postmenopausal women with histologically proven advanced breast cancer
Interventions	Exemestane + celecoxib versus exemestane versus letrozole
Outcomes	Levels of serum lipids and cholesterol
Starting date	February 2002
Contact information	LWC Chow [email protected]
Notes	initial report published in 2005

ECOG E4101

Study name	ECOG E4101
Methods
Participants	Target accrual = 148 postmenopausal women with HR+ metastatic breast cancer previously treated with up to two chemotherapy regimens and/or one prior endocrine therapy
Interventions	Faslodex + gefitinib versus arimidex + gefitinib
Outcomes
Starting date
Contact information	Dr RW Carlson or AstroZeneca
Notes	currently recruiting in the USA

ICR‐CTSU Sofea

Study name	Sofea Phase III
Methods
Participants	Target accrual = 750 women with metastatic disease who have failed after non‐steroidal AI
Interventions	Faslodes versus faslodex + anastrozole versus exemestane
Outcomes
Starting date	March 2004
Contact information	Dr SRD Johnston, Royal Marsden Hospital email: sofea‐[email protected]
Notes	Open to recruitment in UK

Paridaens 2003

Study name	Phase III EORTC‐10951
Methods
Participants	Postmenopausal women with metastatic and progressive disease or locally recurrent and inoperable
Interventions	exemestane versus tamoxifen
Outcomes
Starting date
Contact information	[email protected]
Notes	phase II to phase III study

HR+ HER positive

Data and analyses

Open in table viewer

Comparison 1. AI versus non‐AI

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Overall survival (reported or calculated) Show forest plot	13		HR (IV, Fixed, 95% CI)	0.90 [0.84, 0.97]
Open in figure viewer Analysis 1.1 Comparison 1: AI versus non‐AI, Outcome 1: Overall survival (reported or calculated)
1.1.1 aminoglutethimide (any dose)	4		HR (IV, Fixed, 95% CI)	0.94 [0.80, 1.12]
1.1.2 anastrozole 1 mg	3		HR (IV, Fixed, 95% CI)	0.90 [0.79, 1.03]
1.1.3 exemestane 25 mg	1		HR (IV, Fixed, 95% CI)	0.85 [0.72, 0.99]
1.1.4 fadrozole 2 mg	2		HR (IV, Fixed, 95% CI)	1.04 [0.77, 1.40]
1.1.5 letrozole 2.5 mg	2		HR (IV, Fixed, 95% CI)	0.88 [0.73, 1.05]
1.1.6 vorozole 2.5 mg	1		HR (IV, Fixed, 95% CI)	1.10 [0.49, 2.47]
1.2 Progression‐free survival (reported or calculated) Show forest plot	11		HR (IV, Random, 95% CI)	0.98 [0.84, 1.13]
Open in figure viewer Analysis 1.2 Comparison 1: AI versus non‐AI, Outcome 2: Progression‐free survival (reported or calculated)
1.2.1 aminoglutethimide (any dose)	2		HR (IV, Random, 95% CI)	1.07 [0.73, 1.55]
1.2.2 formestane 250 mg	1		HR (IV, Random, 95% CI)	0.93 [0.68, 1.28]
1.2.3 anastrozole 1 mg	2		HR (IV, Random, 95% CI)	1.05 [0.65, 1.70]
1.2.4 exemestane 25 mg	2		HR (IV, Random, 95% CI)	0.91 [0.72, 1.14]
1.2.5 letrozole 2.5 mg	3		HR (IV, Random, 95% CI)	0.87 [0.68, 1.11]
1.2.6 vorozole 2.5 mg	1		HR (IV, Random, 95% CI)	1.27 [1.04, 1.56]
1.3 Clinical benefit (assessable) Show forest plot	27	8789	Odds Ratio (M‐H, Random, 95% CI)	0.87 [0.77, 0.99]
Open in figure viewer Analysis 1.3 Comparison 1: AI versus non‐AI, Outcome 3: Clinical benefit (assessable)
1.3.1 aminoglutethimide (any dose)	9	1292	Odds Ratio (M‐H, Random, 95% CI)	0.79 [0.63, 1.00]
1.3.2 formestane 250 mg	2	521	Odds Ratio (M‐H, Random, 95% CI)	1.05 [0.59, 1.86]
1.3.3 anastrozole 1 mg	4	2626	Odds Ratio (M‐H, Random, 95% CI)	0.74 [0.48, 1.12]
1.3.4 exemestane 25 mg	3	1356	Odds Ratio (M‐H, Random, 95% CI)	0.86 [0.63, 1.19]
1.3.5 fadrozole 2 mg	4	982	Odds Ratio (M‐H, Random, 95% CI)	1.05 [0.80, 1.38]
1.3.6 letrozole 2.5 mg	4	1637	Odds Ratio (M‐H, Random, 95% CI)	0.77 [0.60, 1.00]
1.3.7 vorozole 2.5 mg	1	375	Odds Ratio (M‐H, Random, 95% CI)	1.35 [0.88, 2.07]
1.4 Objective response (assessable) Show forest plot	31	9595	Odds Ratio (M‐H, Random, 95% CI)	0.88 [0.77, 1.01]
Open in figure viewer Analysis 1.4 Comparison 1: AI versus non‐AI, Outcome 4: Objective response (assessable)
1.4.1 aminoglutethimide (any dose)	11	1545	Odds Ratio (M‐H, Random, 95% CI)	0.83 [0.63, 1.09]
1.4.2 formestane 250 mg	3	1000	Odds Ratio (M‐H, Random, 95% CI)	1.23 [0.92, 1.64]
1.4.3 anastrozole 1 mg	4	2626	Odds Ratio (M‐H, Random, 95% CI)	0.95 [0.77, 1.17]
1.4.4 exemestane 25 mg	3	1356	Odds Ratio (M‐H, Random, 95% CI)	0.67 [0.33, 1.33]
1.4.5 fadrozole 2 mg	5	1056	Odds Ratio (M‐H, Random, 95% CI)	1.18 [0.85, 1.65]
1.4.6 letrozole 2.5 mg	4	1637	Odds Ratio (M‐H, Random, 95% CI)	0.65 [0.51, 0.82]
1.4.7 vorozole 2.5 mg	1	375	Odds Ratio (M‐H, Random, 95% CI)	0.70 [0.34, 1.42]
1.5 Clinical benefit (randomised) Show forest plot	27	9425	Odds Ratio (M‐H, Random, 95% CI)	0.88 [0.78, 0.99]
Open in figure viewer Analysis 1.5 Comparison 1: AI versus non‐AI, Outcome 5: Clinical benefit (randomised)
1.5.1 aminoglutethimide (any dose)	9	1395	Odds Ratio (M‐H, Random, 95% CI)	0.81 [0.65, 1.01]
1.5.2 formestane 250 mg	2	586	Odds Ratio (M‐H, Random, 95% CI)	1.00 [0.58, 1.70]
1.5.3 anastrozole 1 mg	4	2626	Odds Ratio (M‐H, Random, 95% CI)	0.74 [0.48, 1.12]
1.5.4 exemestane 25 mg	3	1584	Odds Ratio (M‐H, Random, 95% CI)	0.88 [0.71, 1.11]
1.5.5 fadrozole 2 mg	4	1000	Odds Ratio (M‐H, Random, 95% CI)	1.08 [0.82, 1.41]
1.5.6 letrozole 2.5 mg	4	1782	Odds Ratio (M‐H, Random, 95% CI)	0.77 [0.61, 0.96]
1.5.7 vorozole 2.5 mg	1	452	Odds Ratio (M‐H, Random, 95% CI)	1.25 [0.83, 1.88]
1.6 Objective response (randomised) Show forest plot	31	10422	Odds Ratio (M‐H, Random, 95% CI)	0.90 [0.78, 1.03]
Open in figure viewer Analysis 1.6 Comparison 1: AI versus non‐AI, Outcome 6: Objective response (randomised)
1.6.1 aminoglutethimide (any dose)	11	1765	Odds Ratio (M‐H, Random, 95% CI)	0.89 [0.66, 1.20]
1.6.2 formestane 250 mg	3	1133	Odds Ratio (M‐H, Random, 95% CI)	1.20 [0.91, 1.60]
1.6.3 anastrozole 1 mg	4	2626	Odds Ratio (M‐H, Random, 95% CI)	0.95 [0.77, 1.17]
1.6.4 exemestane 25 mg	3	1584	Odds Ratio (M‐H, Random, 95% CI)	0.68 [0.37, 1.27]
1.6.5 fadrozole 2 mg	5	1080	Odds Ratio (M‐H, Random, 95% CI)	1.21 [0.87, 1.69]
1.6.6 letrozole 2.5 mg	4	1782	Odds Ratio (M‐H, Random, 95% CI)	0.65 [0.52, 0.82]
1.6.7 vorozole 2.5 mg	1	452	Odds Ratio (M‐H, Random, 95% CI)	0.67 [0.33, 1.37]

Open in table viewer

Comparison 2. AI versus non‐AI: Toxicity

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 hot flushes Show forest plot	20	8306	Odds Ratio (M‐H, Fixed, 95% CI)	1.24 [1.10, 1.41]
Open in figure viewer Analysis 2.1 Comparison 2: AI versus non‐AI: Toxicity, Outcome 1: hot flushes
2.1.1 AI versus tamoxifen	7	2616	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.88, 1.29]
2.1.2 AI versus megestrol acetate	10	3926	Odds Ratio (M‐H, Fixed, 95% CI)	1.73 [1.40, 2.14]
2.1.3 AI versus fulvestrant	2	1546	Odds Ratio (M‐H, Fixed, 95% CI)	1.08 [0.82, 1.42]
2.1.4 AI versus medroxyprogesterone acetate	1	218	Odds Ratio (M‐H, Fixed, 95% CI)	0.20 [0.06, 0.73]
2.2 nausea Show forest plot	18		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.2 Comparison 2: AI versus non‐AI: Toxicity, Outcome 2: nausea
2.2.1 AI versus tamoxifen	6	2548	Odds Ratio (M‐H, Random, 95% CI)	1.29 [0.78, 2.13]
2.2.2 AI versus megestrol acetate	9	3755	Odds Ratio (M‐H, Random, 95% CI)	1.77 [1.33, 2.35]
2.2.3 AI versus medroxyprogesterone acetate	1	53	Odds Ratio (M‐H, Random, 95% CI)	8.19 [0.40, 166.83]
2.2.4 AI versus fulvestrant	2	1539	Odds Ratio (M‐H, Random, 95% CI)	1.01 [0.77, 1.32]
2.3 vomiting Show forest plot	8		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.3 Comparison 2: AI versus non‐AI: Toxicity, Outcome 3: vomiting
2.3.1 AI versus tamoxifen	2	1239	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [0.79, 1.90]
2.3.2 AI versus megestrol acetate	5	2319	Odds Ratio (M‐H, Fixed, 95% CI)	2.03 [1.42, 2.90]
2.3.3 AI versus fulvestrant	1	846	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.60, 1.35]
2.4 diarrhoea Show forest plot	10		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.4 Comparison 2: AI versus non‐AI: Toxicity, Outcome 4: diarrhoea
2.4.1 AI versus tamoxifen	3	2149	Odds Ratio (M‐H, Fixed, 95% CI)	1.64 [1.06, 2.55]
2.4.2 AI versus megestrol acetate	5	1961	Odds Ratio (M‐H, Fixed, 95% CI)	1.48 [1.02, 2.13]
2.4.3 AI versus fulvestrant	2	1090	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [0.79, 1.90]
2.5 rash Show forest plot	15		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.5 Comparison 2: AI versus non‐AI: Toxicity, Outcome 5: rash
2.5.1 AI versus tamoxifen	4	711	Odds Ratio (M‐H, Random, 95% CI)	33.61 [4.71, 239.97]
2.5.2 AI versus megestrol acetate	8	3219	Odds Ratio (M‐H, Random, 95% CI)	2.06 [0.92, 4.62]
2.5.3 AI versus medroxyprogesterone acetate	2	271	Odds Ratio (M‐H, Random, 95% CI)	36.80 [3.35, 404.73]
2.5.4 AI versus fulvestrant	1	397	Odds Ratio (M‐H, Random, 95% CI)	1.39 [0.77, 2.50]
2.6 vaginal bleeding Show forest plot	6		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.6 Comparison 2: AI versus non‐AI: Toxicity, Outcome 6: vaginal bleeding
2.6.1 AI versus tamoxifen	1	1017	Odds Ratio (M‐H, Fixed, 95% CI)	0.45 [0.16, 1.32]
2.6.2 AI versus megestrol acetate	3	1462	Odds Ratio (M‐H, Fixed, 95% CI)	0.22 [0.10, 0.45]
2.6.3 AI versus medroxyprogesterone acetate	2	271	Odds Ratio (M‐H, Fixed, 95% CI)	0.13 [0.02, 0.71]
2.7 thromboembolic Show forest plot	6		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.7 Comparison 2: AI versus non‐AI: Toxicity, Outcome 7: thromboembolic
2.7.1 AI versus tamoxifen	2	1228	Odds Ratio (M‐H, Fixed, 95% CI)	0.48 [0.27, 0.85]
2.7.2 AI versus megestrol acetate	3	863	Odds Ratio (M‐H, Fixed, 95% CI)	0.54 [0.26, 1.10]
2.7.3 AI versus fulvestrant	1	846	Odds Ratio (M‐H, Fixed, 95% CI)	1.14 [0.56, 2.31]
2.8 arthralgia Show forest plot	6		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.8 Comparison 2: AI versus non‐AI: Toxicity, Outcome 8: arthralgia
2.8.1 AI versus tamoxifen	2	1031	Odds Ratio (M‐H, Fixed, 95% CI)	1.14 [0.81, 1.60]
2.8.2 AI versus megestrol acetate	4	1439	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [0.98, 2.00]

Open in table viewer

Comparison 3. Current AIs versus non‐AI

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Overall survival (reported or calculated) Show forest plot	6		HR (IV, Fixed, 95% CI)	0.88 [0.80, 0.96]
Open in figure viewer Analysis 3.1 Comparison 3: Current AIs versus non‐AI, Outcome 1: Overall survival (reported or calculated)
3.1.1 anastrozole 1 mg	3		HR (IV, Fixed, 95% CI)	0.90 [0.79, 1.03]
3.1.2 exemestane 25 mg	1		HR (IV, Fixed, 95% CI)	0.85 [0.72, 0.99]
3.1.3 letrozole 2.5 mg	2		HR (IV, Fixed, 95% CI)	0.88 [0.73, 1.05]
3.2 Progression‐free survival (reported or calculated) Show forest plot	7		HR (IV, Random, 95% CI)	0.93 [0.78, 1.12]
Open in figure viewer Analysis 3.2 Comparison 3: Current AIs versus non‐AI, Outcome 2: Progression‐free survival (reported or calculated)
3.2.1 anastrozole 1 mg	2		HR (IV, Random, 95% CI)	1.05 [0.65, 1.70]
3.2.2 exemestane 25 mg	2		HR (IV, Random, 95% CI)	0.91 [0.72, 1.14]
3.2.3 letrozole 2.5 mg	3		HR (IV, Random, 95% CI)	0.87 [0.68, 1.11]
3.3 Clinical benefit (assessable) Show forest plot	11	5619	Odds Ratio (M‐H, Random, 95% CI)	0.80 [0.66, 0.97]
Open in figure viewer Analysis 3.3 Comparison 3: Current AIs versus non‐AI, Outcome 3: Clinical benefit (assessable)
3.3.1 anastrozole 1 mg	4	2626	Odds Ratio (M‐H, Random, 95% CI)	0.74 [0.48, 1.12]
3.3.2 exemestane 25 mg	3	1356	Odds Ratio (M‐H, Random, 95% CI)	0.86 [0.63, 1.19]
3.3.3 letrozole 2.5 mg	4	1637	Odds Ratio (M‐H, Random, 95% CI)	0.77 [0.60, 1.00]
3.4 Objective response (assessable) Show forest plot	11	5619	Odds Ratio (M‐H, Random, 95% CI)	0.79 [0.65, 0.97]
Open in figure viewer Analysis 3.4 Comparison 3: Current AIs versus non‐AI, Outcome 4: Objective response (assessable)
3.4.1 anastrozole 1 mg	4	2626	Odds Ratio (M‐H, Random, 95% CI)	0.95 [0.77, 1.17]
3.4.2 exemestane 25 mg	3	1356	Odds Ratio (M‐H, Random, 95% CI)	0.67 [0.33, 1.33]
3.4.3 letrozole 2.5 mg	4	1637	Odds Ratio (M‐H, Random, 95% CI)	0.65 [0.51, 0.82]
3.5 Clinical benefit (randomised) Show forest plot	11	5992	Odds Ratio (M‐H, Random, 95% CI)	0.81 [0.67, 0.97]
Open in figure viewer Analysis 3.5 Comparison 3: Current AIs versus non‐AI, Outcome 5: Clinical benefit (randomised)
3.5.1 anastrozole 1 mg	4	2626	Odds Ratio (M‐H, Random, 95% CI)	0.74 [0.48, 1.12]
3.5.2 exemestane 25 mg	3	1584	Odds Ratio (M‐H, Random, 95% CI)	0.88 [0.71, 1.11]
3.5.3 letrozole 2.5 mg	4	1782	Odds Ratio (M‐H, Random, 95% CI)	0.77 [0.61, 0.96]
3.6 Objective response (randomised) Show forest plot	11	5992	Odds Ratio (M‐H, Random, 95% CI)	0.80 [0.66, 0.96]
Open in figure viewer Analysis 3.6 Comparison 3: Current AIs versus non‐AI, Outcome 6: Objective response (randomised)
3.6.1 anastrozole 1 mg	4	2626	Odds Ratio (M‐H, Random, 95% CI)	0.95 [0.77, 1.17]
3.6.2 exemestane 25 mg	3	1584	Odds Ratio (M‐H, Random, 95% CI)	0.68 [0.37, 1.27]
3.6.3 letrozole 2.5 mg	4	1782	Odds Ratio (M‐H, Random, 95% CI)	0.65 [0.52, 0.82]

Open in table viewer

Comparison 4. Current AIs versus non‐AI: Toxicity

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 hot flushes Show forest plot	9		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.1 Comparison 4: Current AIs versus non‐AI: Toxicity, Outcome 1: hot flushes
4.1.1 AI versus tamoxifen	3	2048	Odds Ratio (M‐H, Fixed, 95% CI)	1.13 [0.91, 1.39]
4.1.2 AI versus megestrol acetate	4	2036	Odds Ratio (M‐H, Fixed, 95% CI)	1.69 [1.24, 2.30]
4.1.3 AI versus fulvestrant	2	1539	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.81, 1.41]
4.2 nausea Show forest plot	9		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.2 Comparison 4: Current AIs versus non‐AI: Toxicity, Outcome 2: nausea
4.2.1 AI versus tamoxifen	3	2048	Odds Ratio (M‐H, Fixed, 95% CI)	0.89 [0.72, 1.11]
4.2.2 AI versus megestrol acetate	4	2036	Odds Ratio (M‐H, Fixed, 95% CI)	1.45 [1.09, 1.95]
4.2.3 AI versus fulvestrant	2	1539	Odds Ratio (M‐H, Fixed, 95% CI)	1.01 [0.77, 1.32]
4.3 vomiting Show forest plot	5		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.3 Comparison 4: Current AIs versus non‐AI: Toxicity, Outcome 3: vomiting
4.3.1 AI versus tamoxifen	1	1017	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.67, 1.72]
4.3.2 AI versus megestrol acetate	3	1636	Odds Ratio (M‐H, Fixed, 95% CI)	1.77 [1.11, 2.83]
4.3.3 AI versus fulvestrant	1	846	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.60, 1.35]
4.4 diarrhoea Show forest plot	7		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.4 Comparison 4: Current AIs versus non‐AI: Toxicity, Outcome 4: diarrhoea
4.4.1 AI versus tamoxifen	2	1927	Odds Ratio (M‐H, Fixed, 95% CI)	1.49 [0.95, 2.35]
4.4.2 AI versus megestrol acetate	3	1278	Odds Ratio (M‐H, Fixed, 95% CI)	2.40 [1.34, 4.29]
4.4.3 AI versus fulvestrant	2	1090	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [0.79, 1.90]
4.5 rash Show forest plot	4		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.5 Comparison 4: Current AIs versus non‐AI: Toxicity, Outcome 5: rash
4.5.1 AI versus megestrol acetate	3	1636	Odds Ratio (M‐H, Random, 95% CI)	1.63 [0.47, 5.70]
4.5.2 AI versus fulvestrant	1	397	Odds Ratio (M‐H, Random, 95% CI)	1.39 [0.77, 2.50]
4.6 vaginal bleeding Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.6 Comparison 4: Current AIs versus non‐AI: Toxicity, Outcome 6: vaginal bleeding
4.6.1 AI versus tamoxifen	1	1017	Odds Ratio (M‐H, Fixed, 95% CI)	0.45 [0.16, 1.32]
4.6.2 AI versus megestrol acetate	2	915	Odds Ratio (M‐H, Fixed, 95% CI)	0.29 [0.13, 0.65]
4.7 thromboembolic Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.7 Comparison 4: Current AIs versus non‐AI: Toxicity, Outcome 7: thromboembolic
4.7.1 AI versus tamoxifen	1	1017	Odds Ratio (M‐H, Fixed, 95% CI)	0.53 [0.30, 0.96]
4.7.2 AI versus megestrol acetate	1	515	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.30, 1.73]
4.7.3 AI versus fulvestrant	1	846	Odds Ratio (M‐H, Fixed, 95% CI)	1.14 [0.56, 2.31]
4.8 arthralgia Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.8 Comparison 4: Current AIs versus non‐AI: Toxicity, Outcome 8: arthralgia
4.8.1 AI versus tamoxifen	2	1031	Odds Ratio (M‐H, Fixed, 95% CI)	1.14 [0.81, 1.60]
4.8.2 AI versus megestrol acetate	1	363	Odds Ratio (M‐H, Fixed, 95% CI)	1.77 [0.89, 3.51]

Open in table viewer

Comparison 5. AI versus different AI

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Overall survival (reported) Show forest plot	2		HR (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 5.1 Comparison 5: AI versus different AI, Outcome 1: Overall survival (reported)
5.1.1 letrozole	2		HR (IV, Fixed, 95% CI)	0.91 [0.82, 1.02]
5.2 Progession‐free survival (reported or calculated) Show forest plot	2		HR (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 5.2 Comparison 5: AI versus different AI, Outcome 2: Progession‐free survival (reported or calculated)
5.2.1 letrozole	2		HR (IV, Fixed, 95% CI)	0.97 [0.90, 1.04]
5.3 Clinical benefit (assessable) Show forest plot	5		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 5.3 Comparison 5: AI versus different AI, Outcome 3: Clinical benefit (assessable)
5.3.1 letrozole	4	1687	Odds Ratio (M‐H, Fixed, 95% CI)	0.77 [0.62, 0.95]
5.3.2 anastrozole	2	663	Odds Ratio (M‐H, Fixed, 95% CI)	1.29 [0.92, 1.79]
5.4 Objective response (assessable) Show forest plot	5		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 5.4 Comparison 5: AI versus different AI, Outcome 4: Objective response (assessable)
5.4.1 letrozole	4	1687	Odds Ratio (M‐H, Fixed, 95% CI)	0.62 [0.50, 0.78]
5.4.2 anastrozole	2	663	Odds Ratio (M‐H, Fixed, 95% CI)	1.59 [1.07, 2.37]
5.5 Clinical benefit (randomised) Show forest plot	5		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 5.5 Comparison 5: AI versus different AI, Outcome 5: Clinical benefit (randomised)
5.5.1 letrozole	4	2098	Odds Ratio (M‐H, Fixed, 95% CI)	0.82 [0.68, 0.98]
5.5.2 anastrozole	2	773	Odds Ratio (M‐H, Fixed, 95% CI)	1.25 [0.90, 1.72]
5.6 Objective response (randomised) Show forest plot	5		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 5.6 Comparison 5: AI versus different AI, Outcome 6: Objective response (randomised)
5.6.1 letrozole	4	2098	Odds Ratio (M‐H, Fixed, 95% CI)	0.66 [0.54, 0.82]
5.6.2 anastrozole	2	782	Odds Ratio (M‐H, Fixed, 95% CI)	1.50 [1.01, 2.23]

Open in table viewer

Comparison 6. AI as first‐line therapy versus any other therapy (tamoxifen)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Overall survival (reported or calculated) Show forest plot	3		HR (IV, Fixed, 95% CI)	0.99 [0.86, 1.14]
Open in figure viewer Analysis 6.1 Comparison 6: AI as first‐line therapy versus any other therapy (tamoxifen), Outcome 1: Overall survival (reported or calculated)
6.1.1 aminoglutethimide as first‐line therapy	1		HR (IV, Fixed, 95% CI)	1.12 [0.82, 1.53]
6.1.2 anastrozole as first‐line therapy	1		HR (IV, Fixed, 95% CI)	0.97 [0.81, 1.16]
6.1.3 fadrozole as first‐line therapy	1		HR (IV, Fixed, 95% CI)	0.91 [0.63, 1.32]
6.2 Progression‐free survival (reported or calculated) Show forest plot	4		HR (IV, Fixed, 95% CI)	0.78 [0.71, 0.86]
Open in figure viewer Analysis 6.2 Comparison 6: AI as first‐line therapy versus any other therapy (tamoxifen), Outcome 2: Progression‐free survival (reported or calculated)
6.2.1 aminoglutethimide	1		HR (IV, Fixed, 95% CI)	0.84 [0.65, 1.08]
6.2.2 formestane as first‐line therapy	1		HR (IV, Fixed, 95% CI)	0.93 [0.68, 1.28]
6.2.3 anastrozole as first‐line therapy	1		HR (IV, Fixed, 95% CI)	0.82 [0.71, 0.95]
6.2.4 letrozole as first‐line therapy	1		HR (IV, Fixed, 95% CI)	0.70 [0.60, 0.82]
6.3 Clinical benefit (assessable) Show forest plot	9	3252	Odds Ratio (M‐H, Random, 95% CI)	0.69 [0.51, 0.92]
Open in figure viewer Analysis 6.3 Comparison 6: AI as first‐line therapy versus any other therapy (tamoxifen), Outcome 3: Clinical benefit (assessable)
6.3.1 aminoglutethimide (any dose)	3	479	Odds Ratio (M‐H, Random, 95% CI)	0.63 [0.42, 0.93]
6.3.2 formestane 250 mg	1	348	Odds Ratio (M‐H, Random, 95% CI)	1.36 [0.87, 2.13]
6.3.3 anastrozole 1 mg	2	1259	Odds Ratio (M‐H, Random, 95% CI)	0.48 [0.16, 1.44]
6.3.4 exemestane 25 mg	1	113	Odds Ratio (M‐H, Random, 95% CI)	0.47 [0.22, 0.99]
6.3.5 fadrozole 2 mg	1	209	Odds Ratio (M‐H, Random, 95% CI)	1.09 [0.58, 2.06]
6.3.6 letrozole 2.5 mg	1	844	Odds Ratio (M‐H, Random, 95% CI)	0.63 [0.48, 0.82]
6.4 Objective response (assessable) Show forest plot	11	3503	Odds Ratio (M‐H, Random, 95% CI)	0.77 [0.59, 1.00]
Open in figure viewer Analysis 6.4 Comparison 6: AI as first‐line therapy versus any other therapy (tamoxifen), Outcome 4: Objective response (assessable)
6.4.1 aminoglutethimide (any dose)	4	656	Odds Ratio (M‐H, Random, 95% CI)	0.75 [0.45, 1.25]
6.4.2 formestane 250 mg	1	348	Odds Ratio (M‐H, Random, 95% CI)	1.20 [0.77, 1.87]
6.4.3 anastrozole 1 mg	2	1259	Odds Ratio (M‐H, Random, 95% CI)	0.85 [0.65, 1.11]
6.4.4 exemestane 25 mg	1	113	Odds Ratio (M‐H, Random, 95% CI)	0.26 [0.11, 0.62]
6.4.5 fadrozole 2 mg	2	283	Odds Ratio (M‐H, Random, 95% CI)	1.20 [0.69, 2.09]
6.4.6 letrozole 2.5 mg	1	844	Odds Ratio (M‐H, Random, 95% CI)	0.58 [0.42, 0.78]
6.5 Clinical benefit (randomised) Show forest plot	9	3451	Odds Ratio (M‐H, Random, 95% CI)	0.74 [0.56, 0.98]
Open in figure viewer Analysis 6.5 Comparison 6: AI as first‐line therapy versus any other therapy (tamoxifen), Outcome 5: Clinical benefit (randomised)
6.5.1 aminoglutethimide (any dose)	3	533	Odds Ratio (M‐H, Random, 95% CI)	0.74 [0.51, 1.08]
6.5.2 formestane 250 mg	1	409	Odds Ratio (M‐H, Random, 95% CI)	1.25 [0.85, 1.86]
6.5.3 anastrozole 1 mg	2	1259	Odds Ratio (M‐H, Random, 95% CI)	0.48 [0.16, 1.44]
6.5.4 exemestane 25 mg	1	122	Odds Ratio (M‐H, Random, 95% CI)	0.55 [0.27, 1.13]
6.5.5 fadrozole 2 mg	1	221	Odds Ratio (M‐H, Random, 95% CI)	1.23 [0.69, 2.21]
6.5.6 letrozole 2.5 mg	1	907	Odds Ratio (M‐H, Random, 95% CI)	0.65 [0.50, 0.84]
6.6 Objective response (randomised) Show forest plot	11	3746	Odds Ratio (M‐H, Random, 95% CI)	0.81 [0.62, 1.05]
Open in figure viewer Analysis 6.6 Comparison 6: AI as first‐line therapy versus any other therapy (tamoxifen), Outcome 6: Objective response (randomised)
6.6.1 aminoglutethimide (any dose)	4	748	Odds Ratio (M‐H, Random, 95% CI)	0.83 [0.48, 1.45]
6.6.2 formestane 250 mg	1	409	Odds Ratio (M‐H, Random, 95% CI)	1.18 [0.77, 1.80]
6.6.3 anastrozole 1 mg	2	1259	Odds Ratio (M‐H, Random, 95% CI)	0.85 [0.65, 1.11]
6.6.4 exemestane 25 mg	1	122	Odds Ratio (M‐H, Random, 95% CI)	0.30 [0.13, 0.69]
6.6.5 fadrozole 2 mg	2	301	Odds Ratio (M‐H, Random, 95% CI)	1.28 [0.76, 2.15]
6.6.6 letrozole 2.5 mg	1	907	Odds Ratio (M‐H, Random, 95% CI)	0.59 [0.43, 0.79]

Open in table viewer

Comparison 7. AI as second‐line therapy versus any other therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Overall survival (reported or calculated) Show forest plot	2		HR (IV, Fixed, 95% CI)	0.80 [0.66, 0.96]
Open in figure viewer Analysis 7.1 Comparison 7: AI as second‐line therapy versus any other therapy, Outcome 1: Overall survival (reported or calculated)
7.1.1 anastrozole as second‐line therapy	1		HR (IV, Fixed, 95% CI)	0.78 [0.61, 1.00]
7.1.2 letrozole as second‐line therapy	1		HR (IV, Fixed, 95% CI)	0.82 [0.63, 1.07]
7.2 Progression‐free survival (reported or calculated) Show forest plot	8		HR (IV, Random, 95% CI)	1.08 [0.94, 1.23]
Open in figure viewer Analysis 7.2 Comparison 7: AI as second‐line therapy versus any other therapy, Outcome 2: Progression‐free survival (reported or calculated)
7.2.1 aminoglutethimide (any dose)	1		HR (IV, Random, 95% CI)	1.25 [0.91, 1.72]
7.2.2 formestane 250 mg biweekly	2		HR (IV, Random, 95% CI)	1.03 [0.90, 1.19]
7.2.3 anastrozole 1 mg	1		HR (IV, Random, 95% CI)	1.34 [1.16, 1.55]
7.2.4 exemestane 25 mg	2		HR (IV, Random, 95% CI)	0.91 [0.72, 1.14]
7.2.5 letrozole 2.5 mg	1		HR (IV, Random, 95% CI)	0.98 [0.77, 1.25]
7.2.6 vorozole 2.5 mg	1		HR (IV, Random, 95% CI)	1.27 [1.04, 1.56]
7.3 Clinical benefit (assessable) Show forest plot	16	5410	Odds Ratio (M‐H, Fixed, 95% CI)	0.99 [0.88, 1.11]
Open in figure viewer Analysis 7.3 Comparison 7: AI as second‐line therapy versus any other therapy, Outcome 3: Clinical benefit (assessable)
7.3.1 aminoglutethimide (any dose)	4	686	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.66, 1.23]
7.3.2 formestane 250 mg biweekly	1	173	Odds Ratio (M‐H, Fixed, 95% CI)	0.75 [0.41, 1.39]
7.3.3 anastrozole 1mg	2	1367	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.84, 1.29]
7.3.4 exemestane 25 mg	2	1243	Odds Ratio (M‐H, Fixed, 95% CI)	0.95 [0.75, 1.20]
7.3.5 fadrozole 2 mg	3	773	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.77, 1.41]
7.3.6 letrozole 2.5 mg	3	793	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.68, 1.23]
7.3.7 vorozole 2.5mg	1	375	Odds Ratio (M‐H, Fixed, 95% CI)	1.35 [0.88, 2.07]
7.4 Objective response (assessable) Show forest plot	18	5937	Odds Ratio (M‐H, Fixed, 95% CI)	0.98 [0.86, 1.13]
Open in figure viewer Analysis 7.4 Comparison 7: AI as second‐line therapy versus any other therapy, Outcome 4: Objective response (assessable)
7.4.1 aminoglutethimide (any dose)	5	734	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.68, 1.30]
7.4.2 formestane 250 mg biweekly	2	652	Odds Ratio (M‐H, Fixed, 95% CI)	1.24 [0.84, 1.83]
7.4.3 anastrozole 1 mg	2	1367	Odds Ratio (M‐H, Fixed, 95% CI)	1.12 [0.84, 1.50]
7.4.4 exemestane 25 mg	2	1243	Odds Ratio (M‐H, Fixed, 95% CI)	0.89 [0.63, 1.26]
7.4.5 fadrozole 2 mg	3	773	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.76, 1.80]
7.4.6 letrozole 2.5 mg	3	793	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.53, 1.08]
7.4.7 vorozole 2.5 mg	1	375	Odds Ratio (M‐H, Fixed, 95% CI)	0.70 [0.34, 1.42]
7.5 Clinical benefit (randomised) Show forest plot	16	6432	Odds Ratio (M‐H, Fixed, 95% CI)	1.00 [0.90, 1.11]
Open in figure viewer Analysis 7.5 Comparison 7: AI as second‐line therapy versus any other therapy, Outcome 5: Clinical benefit (randomised)
7.5.1 aminoglutethimide (any dose)	4	1320	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.85, 1.31]
7.5.2 formestane 250 mg biweekly	1	177	Odds Ratio (M‐H, Fixed, 95% CI)	0.72 [0.40, 1.31]
7.5.3 anastrozole 1 mg	2	1367	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.84, 1.29]
7.5.4 exemestane 25 mg	2	1462	Odds Ratio (M‐H, Fixed, 95% CI)	0.93 [0.74, 1.16]
7.5.5 fadrozole 2 mg	3	779	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.77, 1.41]
7.5.6 letrozole 2.5 mg	3	875	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.68, 1.21]
7.5.7 vorozole 2.5mg	1	452	Odds Ratio (M‐H, Fixed, 95% CI)	1.25 [0.83, 1.88]
7.6 Objective response (randomised) Show forest plot	18	7113	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.92, 1.18]
Open in figure viewer Analysis 7.6 Comparison 7: AI as second‐line therapy versus any other therapy, Outcome 6: Objective response (randomised)
7.6.1 aminoglutethimide (any dose)	5	1475	Odds Ratio (M‐H, Fixed, 95% CI)	1.15 [0.91, 1.45]
7.6.2 formestane 250 mg biweekly	2	724	Odds Ratio (M‐H, Fixed, 95% CI)	1.22 [0.84, 1.79]
7.6.3 anastrozole 1 mg	2	1367	Odds Ratio (M‐H, Fixed, 95% CI)	1.12 [0.84, 1.50]
7.6.4 exemestane 25 mg	2	1462	Odds Ratio (M‐H, Fixed, 95% CI)	0.87 [0.62, 1.24]
7.6.5 fadrozole 2 mg	3	779	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.76, 1.80]
7.6.6 letrozole 2.5 mg	3	854	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.56, 1.13]
7.6.7 vorozole 2.5 mg	1	452	Odds Ratio (M‐H, Fixed, 95% CI)	0.67 [0.33, 1.37]

Analysis 1.1

Comparison 1: AI versus non‐AI, Outcome 1: Overall survival (reported or calculated)

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Analysis 1.2

Comparison 1: AI versus non‐AI, Outcome 2: Progression‐free survival (reported or calculated)

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Analysis 1.3

Comparison 1: AI versus non‐AI, Outcome 3: Clinical benefit (assessable)

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Analysis 1.4

Comparison 1: AI versus non‐AI, Outcome 4: Objective response (assessable)

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Analysis 1.5

Comparison 1: AI versus non‐AI, Outcome 5: Clinical benefit (randomised)

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Analysis 1.6

Comparison 1: AI versus non‐AI, Outcome 6: Objective response (randomised)

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Analysis 2.1

Comparison 2: AI versus non‐AI: Toxicity, Outcome 1: hot flushes

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Analysis 2.2

Comparison 2: AI versus non‐AI: Toxicity, Outcome 2: nausea

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Analysis 2.3

Comparison 2: AI versus non‐AI: Toxicity, Outcome 3: vomiting

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Analysis 2.4

Comparison 2: AI versus non‐AI: Toxicity, Outcome 4: diarrhoea

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Analysis 2.5

Comparison 2: AI versus non‐AI: Toxicity, Outcome 5: rash

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Analysis 2.6

Comparison 2: AI versus non‐AI: Toxicity, Outcome 6: vaginal bleeding

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Analysis 2.7

Comparison 2: AI versus non‐AI: Toxicity, Outcome 7: thromboembolic

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Analysis 2.8

Comparison 2: AI versus non‐AI: Toxicity, Outcome 8: arthralgia

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Analysis 3.1

Comparison 3: Current AIs versus non‐AI, Outcome 1: Overall survival (reported or calculated)

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Analysis 3.2

Comparison 3: Current AIs versus non‐AI, Outcome 2: Progression‐free survival (reported or calculated)

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Analysis 3.3

Comparison 3: Current AIs versus non‐AI, Outcome 3: Clinical benefit (assessable)

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Analysis 3.4

Comparison 3: Current AIs versus non‐AI, Outcome 4: Objective response (assessable)

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Analysis 3.5

Comparison 3: Current AIs versus non‐AI, Outcome 5: Clinical benefit (randomised)

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Analysis 3.6

Comparison 3: Current AIs versus non‐AI, Outcome 6: Objective response (randomised)

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Analysis 4.1

Comparison 4: Current AIs versus non‐AI: Toxicity, Outcome 1: hot flushes

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Analysis 4.2

Comparison 4: Current AIs versus non‐AI: Toxicity, Outcome 2: nausea

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Analysis 4.3

Comparison 4: Current AIs versus non‐AI: Toxicity, Outcome 3: vomiting

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Analysis 4.4

Comparison 4: Current AIs versus non‐AI: Toxicity, Outcome 4: diarrhoea

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Analysis 4.5

Comparison 4: Current AIs versus non‐AI: Toxicity, Outcome 5: rash

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Analysis 4.6

Comparison 4: Current AIs versus non‐AI: Toxicity, Outcome 6: vaginal bleeding

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Analysis 4.7

Comparison 4: Current AIs versus non‐AI: Toxicity, Outcome 7: thromboembolic

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Analysis 4.8

Comparison 4: Current AIs versus non‐AI: Toxicity, Outcome 8: arthralgia

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Analysis 5.1

Comparison 5: AI versus different AI, Outcome 1: Overall survival (reported)

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Analysis 5.2

Comparison 5: AI versus different AI, Outcome 2: Progession‐free survival (reported or calculated)

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Analysis 5.3

Comparison 5: AI versus different AI, Outcome 3: Clinical benefit (assessable)

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Analysis 5.4

Comparison 5: AI versus different AI, Outcome 4: Objective response (assessable)

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Analysis 5.5

Comparison 5: AI versus different AI, Outcome 5: Clinical benefit (randomised)

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Analysis 5.6

Comparison 5: AI versus different AI, Outcome 6: Objective response (randomised)

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Analysis 6.1

Comparison 6: AI as first‐line therapy versus any other therapy (tamoxifen), Outcome 1: Overall survival (reported or calculated)

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Analysis 6.2

Comparison 6: AI as first‐line therapy versus any other therapy (tamoxifen), Outcome 2: Progression‐free survival (reported or calculated)

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Analysis 6.3

Comparison 6: AI as first‐line therapy versus any other therapy (tamoxifen), Outcome 3: Clinical benefit (assessable)

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Analysis 6.4

Comparison 6: AI as first‐line therapy versus any other therapy (tamoxifen), Outcome 4: Objective response (assessable)

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Analysis 6.5

Comparison 6: AI as first‐line therapy versus any other therapy (tamoxifen), Outcome 5: Clinical benefit (randomised)

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Analysis 6.6

Comparison 6: AI as first‐line therapy versus any other therapy (tamoxifen), Outcome 6: Objective response (randomised)

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Analysis 7.1

Comparison 7: AI as second‐line therapy versus any other therapy, Outcome 1: Overall survival (reported or calculated)

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Analysis 7.2

Comparison 7: AI as second‐line therapy versus any other therapy, Outcome 2: Progression‐free survival (reported or calculated)

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Analysis 7.3

Comparison 7: AI as second‐line therapy versus any other therapy, Outcome 3: Clinical benefit (assessable)

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Analysis 7.4

Comparison 7: AI as second‐line therapy versus any other therapy, Outcome 4: Objective response (assessable)

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Analysis 7.5

Comparison 7: AI as second‐line therapy versus any other therapy, Outcome 5: Clinical benefit (randomised)

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Analysis 7.6

Comparison 7: AI as second‐line therapy versus any other therapy, Outcome 6: Objective response (randomised)

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Table 1. Aromatase inhibitors ‐ description

Generic Name	Trade Name	Generation	Doses used
aminoglutethimide		First	125 mg, 250 mg, 500 mg, 750 mg, 1000 mg
anastrozole	Arimidex	Third, non‐steroidal	1 mg, 10 mg
atamestane		Third, steroidal	500mg
exemestane	Aromasin	Third, steroidal	25 mg
fadrozole	CGS16949A	Third, non‐steroidal	2 mg
formestane	Lentaron	Second	250 mg im
letrozole	Femara	Third, non‐steroidal	0.5 mg, 2 mg, 2.5 mg, 10 mg
vorozole		Third, non‐steroidal	2.5 mg

Table 1. Aromatase inhibitors ‐ description

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Comparison 1. AI versus non‐AI

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Overall survival (reported or calculated) Show forest plot	13		HR (IV, Fixed, 95% CI)	0.90 [0.84, 0.97]

1.1.1 aminoglutethimide (any dose)	4		HR (IV, Fixed, 95% CI)	0.94 [0.80, 1.12]
1.1.2 anastrozole 1 mg	3		HR (IV, Fixed, 95% CI)	0.90 [0.79, 1.03]
1.1.3 exemestane 25 mg	1		HR (IV, Fixed, 95% CI)	0.85 [0.72, 0.99]
1.1.4 fadrozole 2 mg	2		HR (IV, Fixed, 95% CI)	1.04 [0.77, 1.40]
1.1.5 letrozole 2.5 mg	2		HR (IV, Fixed, 95% CI)	0.88 [0.73, 1.05]
1.1.6 vorozole 2.5 mg	1		HR (IV, Fixed, 95% CI)	1.10 [0.49, 2.47]
1.2 Progression‐free survival (reported or calculated) Show forest plot	11		HR (IV, Random, 95% CI)	0.98 [0.84, 1.13]

1.2.1 aminoglutethimide (any dose)	2		HR (IV, Random, 95% CI)	1.07 [0.73, 1.55]
1.2.2 formestane 250 mg	1		HR (IV, Random, 95% CI)	0.93 [0.68, 1.28]
1.2.3 anastrozole 1 mg	2		HR (IV, Random, 95% CI)	1.05 [0.65, 1.70]
1.2.4 exemestane 25 mg	2		HR (IV, Random, 95% CI)	0.91 [0.72, 1.14]
1.2.5 letrozole 2.5 mg	3		HR (IV, Random, 95% CI)	0.87 [0.68, 1.11]
1.2.6 vorozole 2.5 mg	1		HR (IV, Random, 95% CI)	1.27 [1.04, 1.56]
1.3 Clinical benefit (assessable) Show forest plot	27	8789	Odds Ratio (M‐H, Random, 95% CI)	0.87 [0.77, 0.99]

1.3.1 aminoglutethimide (any dose)	9	1292	Odds Ratio (M‐H, Random, 95% CI)	0.79 [0.63, 1.00]
1.3.2 formestane 250 mg	2	521	Odds Ratio (M‐H, Random, 95% CI)	1.05 [0.59, 1.86]
1.3.3 anastrozole 1 mg	4	2626	Odds Ratio (M‐H, Random, 95% CI)	0.74 [0.48, 1.12]
1.3.4 exemestane 25 mg	3	1356	Odds Ratio (M‐H, Random, 95% CI)	0.86 [0.63, 1.19]
1.3.5 fadrozole 2 mg	4	982	Odds Ratio (M‐H, Random, 95% CI)	1.05 [0.80, 1.38]
1.3.6 letrozole 2.5 mg	4	1637	Odds Ratio (M‐H, Random, 95% CI)	0.77 [0.60, 1.00]
1.3.7 vorozole 2.5 mg	1	375	Odds Ratio (M‐H, Random, 95% CI)	1.35 [0.88, 2.07]
1.4 Objective response (assessable) Show forest plot	31	9595	Odds Ratio (M‐H, Random, 95% CI)	0.88 [0.77, 1.01]

1.4.1 aminoglutethimide (any dose)	11	1545	Odds Ratio (M‐H, Random, 95% CI)	0.83 [0.63, 1.09]
1.4.2 formestane 250 mg	3	1000	Odds Ratio (M‐H, Random, 95% CI)	1.23 [0.92, 1.64]
1.4.3 anastrozole 1 mg	4	2626	Odds Ratio (M‐H, Random, 95% CI)	0.95 [0.77, 1.17]
1.4.4 exemestane 25 mg	3	1356	Odds Ratio (M‐H, Random, 95% CI)	0.67 [0.33, 1.33]
1.4.5 fadrozole 2 mg	5	1056	Odds Ratio (M‐H, Random, 95% CI)	1.18 [0.85, 1.65]
1.4.6 letrozole 2.5 mg	4	1637	Odds Ratio (M‐H, Random, 95% CI)	0.65 [0.51, 0.82]
1.4.7 vorozole 2.5 mg	1	375	Odds Ratio (M‐H, Random, 95% CI)	0.70 [0.34, 1.42]
1.5 Clinical benefit (randomised) Show forest plot	27	9425	Odds Ratio (M‐H, Random, 95% CI)	0.88 [0.78, 0.99]

1.5.1 aminoglutethimide (any dose)	9	1395	Odds Ratio (M‐H, Random, 95% CI)	0.81 [0.65, 1.01]
1.5.2 formestane 250 mg	2	586	Odds Ratio (M‐H, Random, 95% CI)	1.00 [0.58, 1.70]
1.5.3 anastrozole 1 mg	4	2626	Odds Ratio (M‐H, Random, 95% CI)	0.74 [0.48, 1.12]
1.5.4 exemestane 25 mg	3	1584	Odds Ratio (M‐H, Random, 95% CI)	0.88 [0.71, 1.11]
1.5.5 fadrozole 2 mg	4	1000	Odds Ratio (M‐H, Random, 95% CI)	1.08 [0.82, 1.41]
1.5.6 letrozole 2.5 mg	4	1782	Odds Ratio (M‐H, Random, 95% CI)	0.77 [0.61, 0.96]
1.5.7 vorozole 2.5 mg	1	452	Odds Ratio (M‐H, Random, 95% CI)	1.25 [0.83, 1.88]
1.6 Objective response (randomised) Show forest plot	31	10422	Odds Ratio (M‐H, Random, 95% CI)	0.90 [0.78, 1.03]

1.6.1 aminoglutethimide (any dose)	11	1765	Odds Ratio (M‐H, Random, 95% CI)	0.89 [0.66, 1.20]
1.6.2 formestane 250 mg	3	1133	Odds Ratio (M‐H, Random, 95% CI)	1.20 [0.91, 1.60]
1.6.3 anastrozole 1 mg	4	2626	Odds Ratio (M‐H, Random, 95% CI)	0.95 [0.77, 1.17]
1.6.4 exemestane 25 mg	3	1584	Odds Ratio (M‐H, Random, 95% CI)	0.68 [0.37, 1.27]
1.6.5 fadrozole 2 mg	5	1080	Odds Ratio (M‐H, Random, 95% CI)	1.21 [0.87, 1.69]
1.6.6 letrozole 2.5 mg	4	1782	Odds Ratio (M‐H, Random, 95% CI)	0.65 [0.52, 0.82]
1.6.7 vorozole 2.5 mg	1	452	Odds Ratio (M‐H, Random, 95% CI)	0.67 [0.33, 1.37]

Comparison 1. AI versus non‐AI

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Comparison 2. AI versus non‐AI: Toxicity

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 hot flushes Show forest plot	20	8306	Odds Ratio (M‐H, Fixed, 95% CI)	1.24 [1.10, 1.41]

2.1.1 AI versus tamoxifen	7	2616	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.88, 1.29]
2.1.2 AI versus megestrol acetate	10	3926	Odds Ratio (M‐H, Fixed, 95% CI)	1.73 [1.40, 2.14]
2.1.3 AI versus fulvestrant	2	1546	Odds Ratio (M‐H, Fixed, 95% CI)	1.08 [0.82, 1.42]
2.1.4 AI versus medroxyprogesterone acetate	1	218	Odds Ratio (M‐H, Fixed, 95% CI)	0.20 [0.06, 0.73]
2.2 nausea Show forest plot	18		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

2.2.1 AI versus tamoxifen	6	2548	Odds Ratio (M‐H, Random, 95% CI)	1.29 [0.78, 2.13]
2.2.2 AI versus megestrol acetate	9	3755	Odds Ratio (M‐H, Random, 95% CI)	1.77 [1.33, 2.35]
2.2.3 AI versus medroxyprogesterone acetate	1	53	Odds Ratio (M‐H, Random, 95% CI)	8.19 [0.40, 166.83]
2.2.4 AI versus fulvestrant	2	1539	Odds Ratio (M‐H, Random, 95% CI)	1.01 [0.77, 1.32]
2.3 vomiting Show forest plot	8		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.3.1 AI versus tamoxifen	2	1239	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [0.79, 1.90]
2.3.2 AI versus megestrol acetate	5	2319	Odds Ratio (M‐H, Fixed, 95% CI)	2.03 [1.42, 2.90]
2.3.3 AI versus fulvestrant	1	846	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.60, 1.35]
2.4 diarrhoea Show forest plot	10		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.4.1 AI versus tamoxifen	3	2149	Odds Ratio (M‐H, Fixed, 95% CI)	1.64 [1.06, 2.55]
2.4.2 AI versus megestrol acetate	5	1961	Odds Ratio (M‐H, Fixed, 95% CI)	1.48 [1.02, 2.13]
2.4.3 AI versus fulvestrant	2	1090	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [0.79, 1.90]
2.5 rash Show forest plot	15		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

2.5.1 AI versus tamoxifen	4	711	Odds Ratio (M‐H, Random, 95% CI)	33.61 [4.71, 239.97]
2.5.2 AI versus megestrol acetate	8	3219	Odds Ratio (M‐H, Random, 95% CI)	2.06 [0.92, 4.62]
2.5.3 AI versus medroxyprogesterone acetate	2	271	Odds Ratio (M‐H, Random, 95% CI)	36.80 [3.35, 404.73]
2.5.4 AI versus fulvestrant	1	397	Odds Ratio (M‐H, Random, 95% CI)	1.39 [0.77, 2.50]
2.6 vaginal bleeding Show forest plot	6		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.6.1 AI versus tamoxifen	1	1017	Odds Ratio (M‐H, Fixed, 95% CI)	0.45 [0.16, 1.32]
2.6.2 AI versus megestrol acetate	3	1462	Odds Ratio (M‐H, Fixed, 95% CI)	0.22 [0.10, 0.45]
2.6.3 AI versus medroxyprogesterone acetate	2	271	Odds Ratio (M‐H, Fixed, 95% CI)	0.13 [0.02, 0.71]
2.7 thromboembolic Show forest plot	6		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.7.1 AI versus tamoxifen	2	1228	Odds Ratio (M‐H, Fixed, 95% CI)	0.48 [0.27, 0.85]
2.7.2 AI versus megestrol acetate	3	863	Odds Ratio (M‐H, Fixed, 95% CI)	0.54 [0.26, 1.10]
2.7.3 AI versus fulvestrant	1	846	Odds Ratio (M‐H, Fixed, 95% CI)	1.14 [0.56, 2.31]
2.8 arthralgia Show forest plot	6		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.8.1 AI versus tamoxifen	2	1031	Odds Ratio (M‐H, Fixed, 95% CI)	1.14 [0.81, 1.60]
2.8.2 AI versus megestrol acetate	4	1439	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [0.98, 2.00]

Comparison 2. AI versus non‐AI: Toxicity

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Comparison 3. Current AIs versus non‐AI

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Overall survival (reported or calculated) Show forest plot	6		HR (IV, Fixed, 95% CI)	0.88 [0.80, 0.96]

3.1.1 anastrozole 1 mg	3		HR (IV, Fixed, 95% CI)	0.90 [0.79, 1.03]
3.1.2 exemestane 25 mg	1		HR (IV, Fixed, 95% CI)	0.85 [0.72, 0.99]
3.1.3 letrozole 2.5 mg	2		HR (IV, Fixed, 95% CI)	0.88 [0.73, 1.05]
3.2 Progression‐free survival (reported or calculated) Show forest plot	7		HR (IV, Random, 95% CI)	0.93 [0.78, 1.12]

3.2.1 anastrozole 1 mg	2		HR (IV, Random, 95% CI)	1.05 [0.65, 1.70]
3.2.2 exemestane 25 mg	2		HR (IV, Random, 95% CI)	0.91 [0.72, 1.14]
3.2.3 letrozole 2.5 mg	3		HR (IV, Random, 95% CI)	0.87 [0.68, 1.11]
3.3 Clinical benefit (assessable) Show forest plot	11	5619	Odds Ratio (M‐H, Random, 95% CI)	0.80 [0.66, 0.97]

3.3.1 anastrozole 1 mg	4	2626	Odds Ratio (M‐H, Random, 95% CI)	0.74 [0.48, 1.12]
3.3.2 exemestane 25 mg	3	1356	Odds Ratio (M‐H, Random, 95% CI)	0.86 [0.63, 1.19]
3.3.3 letrozole 2.5 mg	4	1637	Odds Ratio (M‐H, Random, 95% CI)	0.77 [0.60, 1.00]
3.4 Objective response (assessable) Show forest plot	11	5619	Odds Ratio (M‐H, Random, 95% CI)	0.79 [0.65, 0.97]

3.4.1 anastrozole 1 mg	4	2626	Odds Ratio (M‐H, Random, 95% CI)	0.95 [0.77, 1.17]
3.4.2 exemestane 25 mg	3	1356	Odds Ratio (M‐H, Random, 95% CI)	0.67 [0.33, 1.33]
3.4.3 letrozole 2.5 mg	4	1637	Odds Ratio (M‐H, Random, 95% CI)	0.65 [0.51, 0.82]
3.5 Clinical benefit (randomised) Show forest plot	11	5992	Odds Ratio (M‐H, Random, 95% CI)	0.81 [0.67, 0.97]

3.5.1 anastrozole 1 mg	4	2626	Odds Ratio (M‐H, Random, 95% CI)	0.74 [0.48, 1.12]
3.5.2 exemestane 25 mg	3	1584	Odds Ratio (M‐H, Random, 95% CI)	0.88 [0.71, 1.11]
3.5.3 letrozole 2.5 mg	4	1782	Odds Ratio (M‐H, Random, 95% CI)	0.77 [0.61, 0.96]
3.6 Objective response (randomised) Show forest plot	11	5992	Odds Ratio (M‐H, Random, 95% CI)	0.80 [0.66, 0.96]

3.6.1 anastrozole 1 mg	4	2626	Odds Ratio (M‐H, Random, 95% CI)	0.95 [0.77, 1.17]
3.6.2 exemestane 25 mg	3	1584	Odds Ratio (M‐H, Random, 95% CI)	0.68 [0.37, 1.27]
3.6.3 letrozole 2.5 mg	4	1782	Odds Ratio (M‐H, Random, 95% CI)	0.65 [0.52, 0.82]

Comparison 3. Current AIs versus non‐AI

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Comparison 4. Current AIs versus non‐AI: Toxicity

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 hot flushes Show forest plot	9		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1.1 AI versus tamoxifen	3	2048	Odds Ratio (M‐H, Fixed, 95% CI)	1.13 [0.91, 1.39]
4.1.2 AI versus megestrol acetate	4	2036	Odds Ratio (M‐H, Fixed, 95% CI)	1.69 [1.24, 2.30]
4.1.3 AI versus fulvestrant	2	1539	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.81, 1.41]
4.2 nausea Show forest plot	9		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.2.1 AI versus tamoxifen	3	2048	Odds Ratio (M‐H, Fixed, 95% CI)	0.89 [0.72, 1.11]
4.2.2 AI versus megestrol acetate	4	2036	Odds Ratio (M‐H, Fixed, 95% CI)	1.45 [1.09, 1.95]
4.2.3 AI versus fulvestrant	2	1539	Odds Ratio (M‐H, Fixed, 95% CI)	1.01 [0.77, 1.32]
4.3 vomiting Show forest plot	5		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.3.1 AI versus tamoxifen	1	1017	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.67, 1.72]
4.3.2 AI versus megestrol acetate	3	1636	Odds Ratio (M‐H, Fixed, 95% CI)	1.77 [1.11, 2.83]
4.3.3 AI versus fulvestrant	1	846	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.60, 1.35]
4.4 diarrhoea Show forest plot	7		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.4.1 AI versus tamoxifen	2	1927	Odds Ratio (M‐H, Fixed, 95% CI)	1.49 [0.95, 2.35]
4.4.2 AI versus megestrol acetate	3	1278	Odds Ratio (M‐H, Fixed, 95% CI)	2.40 [1.34, 4.29]
4.4.3 AI versus fulvestrant	2	1090	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [0.79, 1.90]
4.5 rash Show forest plot	4		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only

4.5.1 AI versus megestrol acetate	3	1636	Odds Ratio (M‐H, Random, 95% CI)	1.63 [0.47, 5.70]
4.5.2 AI versus fulvestrant	1	397	Odds Ratio (M‐H, Random, 95% CI)	1.39 [0.77, 2.50]
4.6 vaginal bleeding Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.6.1 AI versus tamoxifen	1	1017	Odds Ratio (M‐H, Fixed, 95% CI)	0.45 [0.16, 1.32]
4.6.2 AI versus megestrol acetate	2	915	Odds Ratio (M‐H, Fixed, 95% CI)	0.29 [0.13, 0.65]
4.7 thromboembolic Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.7.1 AI versus tamoxifen	1	1017	Odds Ratio (M‐H, Fixed, 95% CI)	0.53 [0.30, 0.96]
4.7.2 AI versus megestrol acetate	1	515	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.30, 1.73]
4.7.3 AI versus fulvestrant	1	846	Odds Ratio (M‐H, Fixed, 95% CI)	1.14 [0.56, 2.31]
4.8 arthralgia Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.8.1 AI versus tamoxifen	2	1031	Odds Ratio (M‐H, Fixed, 95% CI)	1.14 [0.81, 1.60]
4.8.2 AI versus megestrol acetate	1	363	Odds Ratio (M‐H, Fixed, 95% CI)	1.77 [0.89, 3.51]

Comparison 4. Current AIs versus non‐AI: Toxicity

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Comparison 5. AI versus different AI

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Overall survival (reported) Show forest plot	2		HR (IV, Fixed, 95% CI)	Subtotals only

5.1.1 letrozole	2		HR (IV, Fixed, 95% CI)	0.91 [0.82, 1.02]
5.2 Progession‐free survival (reported or calculated) Show forest plot	2		HR (IV, Fixed, 95% CI)	Subtotals only

5.2.1 letrozole	2		HR (IV, Fixed, 95% CI)	0.97 [0.90, 1.04]
5.3 Clinical benefit (assessable) Show forest plot	5		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.3.1 letrozole	4	1687	Odds Ratio (M‐H, Fixed, 95% CI)	0.77 [0.62, 0.95]
5.3.2 anastrozole	2	663	Odds Ratio (M‐H, Fixed, 95% CI)	1.29 [0.92, 1.79]
5.4 Objective response (assessable) Show forest plot	5		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.4.1 letrozole	4	1687	Odds Ratio (M‐H, Fixed, 95% CI)	0.62 [0.50, 0.78]
5.4.2 anastrozole	2	663	Odds Ratio (M‐H, Fixed, 95% CI)	1.59 [1.07, 2.37]
5.5 Clinical benefit (randomised) Show forest plot	5		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.5.1 letrozole	4	2098	Odds Ratio (M‐H, Fixed, 95% CI)	0.82 [0.68, 0.98]
5.5.2 anastrozole	2	773	Odds Ratio (M‐H, Fixed, 95% CI)	1.25 [0.90, 1.72]
5.6 Objective response (randomised) Show forest plot	5		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.6.1 letrozole	4	2098	Odds Ratio (M‐H, Fixed, 95% CI)	0.66 [0.54, 0.82]
5.6.2 anastrozole	2	782	Odds Ratio (M‐H, Fixed, 95% CI)	1.50 [1.01, 2.23]

Comparison 5. AI versus different AI

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Comparison 6. AI as first‐line therapy versus any other therapy (tamoxifen)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Overall survival (reported or calculated) Show forest plot	3		HR (IV, Fixed, 95% CI)	0.99 [0.86, 1.14]

6.1.1 aminoglutethimide as first‐line therapy	1		HR (IV, Fixed, 95% CI)	1.12 [0.82, 1.53]
6.1.2 anastrozole as first‐line therapy	1		HR (IV, Fixed, 95% CI)	0.97 [0.81, 1.16]
6.1.3 fadrozole as first‐line therapy	1		HR (IV, Fixed, 95% CI)	0.91 [0.63, 1.32]
6.2 Progression‐free survival (reported or calculated) Show forest plot	4		HR (IV, Fixed, 95% CI)	0.78 [0.71, 0.86]

6.2.1 aminoglutethimide	1		HR (IV, Fixed, 95% CI)	0.84 [0.65, 1.08]
6.2.2 formestane as first‐line therapy	1		HR (IV, Fixed, 95% CI)	0.93 [0.68, 1.28]
6.2.3 anastrozole as first‐line therapy	1		HR (IV, Fixed, 95% CI)	0.82 [0.71, 0.95]
6.2.4 letrozole as first‐line therapy	1		HR (IV, Fixed, 95% CI)	0.70 [0.60, 0.82]
6.3 Clinical benefit (assessable) Show forest plot	9	3252	Odds Ratio (M‐H, Random, 95% CI)	0.69 [0.51, 0.92]

6.3.1 aminoglutethimide (any dose)	3	479	Odds Ratio (M‐H, Random, 95% CI)	0.63 [0.42, 0.93]
6.3.2 formestane 250 mg	1	348	Odds Ratio (M‐H, Random, 95% CI)	1.36 [0.87, 2.13]
6.3.3 anastrozole 1 mg	2	1259	Odds Ratio (M‐H, Random, 95% CI)	0.48 [0.16, 1.44]
6.3.4 exemestane 25 mg	1	113	Odds Ratio (M‐H, Random, 95% CI)	0.47 [0.22, 0.99]
6.3.5 fadrozole 2 mg	1	209	Odds Ratio (M‐H, Random, 95% CI)	1.09 [0.58, 2.06]
6.3.6 letrozole 2.5 mg	1	844	Odds Ratio (M‐H, Random, 95% CI)	0.63 [0.48, 0.82]
6.4 Objective response (assessable) Show forest plot	11	3503	Odds Ratio (M‐H, Random, 95% CI)	0.77 [0.59, 1.00]

6.4.1 aminoglutethimide (any dose)	4	656	Odds Ratio (M‐H, Random, 95% CI)	0.75 [0.45, 1.25]
6.4.2 formestane 250 mg	1	348	Odds Ratio (M‐H, Random, 95% CI)	1.20 [0.77, 1.87]
6.4.3 anastrozole 1 mg	2	1259	Odds Ratio (M‐H, Random, 95% CI)	0.85 [0.65, 1.11]
6.4.4 exemestane 25 mg	1	113	Odds Ratio (M‐H, Random, 95% CI)	0.26 [0.11, 0.62]
6.4.5 fadrozole 2 mg	2	283	Odds Ratio (M‐H, Random, 95% CI)	1.20 [0.69, 2.09]
6.4.6 letrozole 2.5 mg	1	844	Odds Ratio (M‐H, Random, 95% CI)	0.58 [0.42, 0.78]
6.5 Clinical benefit (randomised) Show forest plot	9	3451	Odds Ratio (M‐H, Random, 95% CI)	0.74 [0.56, 0.98]

6.5.1 aminoglutethimide (any dose)	3	533	Odds Ratio (M‐H, Random, 95% CI)	0.74 [0.51, 1.08]
6.5.2 formestane 250 mg	1	409	Odds Ratio (M‐H, Random, 95% CI)	1.25 [0.85, 1.86]
6.5.3 anastrozole 1 mg	2	1259	Odds Ratio (M‐H, Random, 95% CI)	0.48 [0.16, 1.44]
6.5.4 exemestane 25 mg	1	122	Odds Ratio (M‐H, Random, 95% CI)	0.55 [0.27, 1.13]
6.5.5 fadrozole 2 mg	1	221	Odds Ratio (M‐H, Random, 95% CI)	1.23 [0.69, 2.21]
6.5.6 letrozole 2.5 mg	1	907	Odds Ratio (M‐H, Random, 95% CI)	0.65 [0.50, 0.84]
6.6 Objective response (randomised) Show forest plot	11	3746	Odds Ratio (M‐H, Random, 95% CI)	0.81 [0.62, 1.05]

6.6.1 aminoglutethimide (any dose)	4	748	Odds Ratio (M‐H, Random, 95% CI)	0.83 [0.48, 1.45]
6.6.2 formestane 250 mg	1	409	Odds Ratio (M‐H, Random, 95% CI)	1.18 [0.77, 1.80]
6.6.3 anastrozole 1 mg	2	1259	Odds Ratio (M‐H, Random, 95% CI)	0.85 [0.65, 1.11]
6.6.4 exemestane 25 mg	1	122	Odds Ratio (M‐H, Random, 95% CI)	0.30 [0.13, 0.69]
6.6.5 fadrozole 2 mg	2	301	Odds Ratio (M‐H, Random, 95% CI)	1.28 [0.76, 2.15]
6.6.6 letrozole 2.5 mg	1	907	Odds Ratio (M‐H, Random, 95% CI)	0.59 [0.43, 0.79]

Comparison 6. AI as first‐line therapy versus any other therapy (tamoxifen)

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Comparison 7. AI as second‐line therapy versus any other therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Overall survival (reported or calculated) Show forest plot	2		HR (IV, Fixed, 95% CI)	0.80 [0.66, 0.96]

7.1.1 anastrozole as second‐line therapy	1		HR (IV, Fixed, 95% CI)	0.78 [0.61, 1.00]
7.1.2 letrozole as second‐line therapy	1		HR (IV, Fixed, 95% CI)	0.82 [0.63, 1.07]
7.2 Progression‐free survival (reported or calculated) Show forest plot	8		HR (IV, Random, 95% CI)	1.08 [0.94, 1.23]

7.2.1 aminoglutethimide (any dose)	1		HR (IV, Random, 95% CI)	1.25 [0.91, 1.72]
7.2.2 formestane 250 mg biweekly	2		HR (IV, Random, 95% CI)	1.03 [0.90, 1.19]
7.2.3 anastrozole 1 mg	1		HR (IV, Random, 95% CI)	1.34 [1.16, 1.55]
7.2.4 exemestane 25 mg	2		HR (IV, Random, 95% CI)	0.91 [0.72, 1.14]
7.2.5 letrozole 2.5 mg	1		HR (IV, Random, 95% CI)	0.98 [0.77, 1.25]
7.2.6 vorozole 2.5 mg	1		HR (IV, Random, 95% CI)	1.27 [1.04, 1.56]
7.3 Clinical benefit (assessable) Show forest plot	16	5410	Odds Ratio (M‐H, Fixed, 95% CI)	0.99 [0.88, 1.11]

7.3.1 aminoglutethimide (any dose)	4	686	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.66, 1.23]
7.3.2 formestane 250 mg biweekly	1	173	Odds Ratio (M‐H, Fixed, 95% CI)	0.75 [0.41, 1.39]
7.3.3 anastrozole 1mg	2	1367	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.84, 1.29]
7.3.4 exemestane 25 mg	2	1243	Odds Ratio (M‐H, Fixed, 95% CI)	0.95 [0.75, 1.20]
7.3.5 fadrozole 2 mg	3	773	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.77, 1.41]
7.3.6 letrozole 2.5 mg	3	793	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.68, 1.23]
7.3.7 vorozole 2.5mg	1	375	Odds Ratio (M‐H, Fixed, 95% CI)	1.35 [0.88, 2.07]
7.4 Objective response (assessable) Show forest plot	18	5937	Odds Ratio (M‐H, Fixed, 95% CI)	0.98 [0.86, 1.13]

7.4.1 aminoglutethimide (any dose)	5	734	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.68, 1.30]
7.4.2 formestane 250 mg biweekly	2	652	Odds Ratio (M‐H, Fixed, 95% CI)	1.24 [0.84, 1.83]
7.4.3 anastrozole 1 mg	2	1367	Odds Ratio (M‐H, Fixed, 95% CI)	1.12 [0.84, 1.50]
7.4.4 exemestane 25 mg	2	1243	Odds Ratio (M‐H, Fixed, 95% CI)	0.89 [0.63, 1.26]
7.4.5 fadrozole 2 mg	3	773	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.76, 1.80]
7.4.6 letrozole 2.5 mg	3	793	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.53, 1.08]
7.4.7 vorozole 2.5 mg	1	375	Odds Ratio (M‐H, Fixed, 95% CI)	0.70 [0.34, 1.42]
7.5 Clinical benefit (randomised) Show forest plot	16	6432	Odds Ratio (M‐H, Fixed, 95% CI)	1.00 [0.90, 1.11]

7.5.1 aminoglutethimide (any dose)	4	1320	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.85, 1.31]
7.5.2 formestane 250 mg biweekly	1	177	Odds Ratio (M‐H, Fixed, 95% CI)	0.72 [0.40, 1.31]
7.5.3 anastrozole 1 mg	2	1367	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.84, 1.29]
7.5.4 exemestane 25 mg	2	1462	Odds Ratio (M‐H, Fixed, 95% CI)	0.93 [0.74, 1.16]
7.5.5 fadrozole 2 mg	3	779	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.77, 1.41]
7.5.6 letrozole 2.5 mg	3	875	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.68, 1.21]
7.5.7 vorozole 2.5mg	1	452	Odds Ratio (M‐H, Fixed, 95% CI)	1.25 [0.83, 1.88]
7.6 Objective response (randomised) Show forest plot	18	7113	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.92, 1.18]

7.6.1 aminoglutethimide (any dose)	5	1475	Odds Ratio (M‐H, Fixed, 95% CI)	1.15 [0.91, 1.45]
7.6.2 formestane 250 mg biweekly	2	724	Odds Ratio (M‐H, Fixed, 95% CI)	1.22 [0.84, 1.79]
7.6.3 anastrozole 1 mg	2	1367	Odds Ratio (M‐H, Fixed, 95% CI)	1.12 [0.84, 1.50]
7.6.4 exemestane 25 mg	2	1462	Odds Ratio (M‐H, Fixed, 95% CI)	0.87 [0.62, 1.24]
7.6.5 fadrozole 2 mg	3	779	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.76, 1.80]
7.6.6 letrozole 2.5 mg	3	854	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.56, 1.13]
7.6.7 vorozole 2.5 mg	1	452	Odds Ratio (M‐H, Fixed, 95% CI)	0.67 [0.33, 1.37]

Comparison 7. AI as second‐line therapy versus any other therapy

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Referencias

Referencias de los estudios incluidos en esta revisión

Alonso‐Munoz 1988 {published data only}

Bezwoda 1998 {published data only}

Bonneterre 2001 {published data only}

Buzdar 1996a {published data only}

Buzdar 1996b {published data only}

Buzdar 1996c {published data only}

Buzdar 2001 {published data only}

Canney 1988 {published data only}

Chia 2008 {published data only}

Dombernowsky 1998 {published data only}

Falkson 1996 {published data only}

Freue 2000 {published data only}

Gale 1994 {published data only}

Garcia‐Giralt 1992 {published data only}

Gershanovich 1998 {published data only}

Goss 1999 {published data only}

Goss 2007 {published data only}

Ingle 1986 {published data only}

Kaufmann 2000 {published data only}

Kleeberg 1997 {published data only}

Leitzel 1995 {published data only}

Lundgren 1989 {published data only}

Mauriac 2003 {published data only}

Mercer 1993 {published data only}

Milla‐Santos 2003 {published data only}

Mourisden 2001 {published data only}

Paridaens 2003 {published data only}

Perez Carrion 1994 {published data only}

Powles 1984 {published data only}

Rose 1986 {published data only}

Rose 2003 {published data only}

Russell 1997 {published data only}

Samonis 1994 {published data only}

Schmid 2001 {published data only}

Thuerlimann 1996 {published data only}

Thuerlimann 1997 {published data only}

Tominaga 2003 {published data only}

Referencias de los estudios excluidos de esta revisión

Abe 2002 {published data only}

Bajetta 1994 {published data only}

Bajetta 1997 {published data only}

Bajetta 1997a {published data only}

Bajetta 1999 {published data only}

Beretta 1990 {published data only}

Bruning 1989 {published data only}

Bruning 1990 {published data only}

Castelazo 2004 {published data only}

Cataliotti 2006 {published data only}

Dixon 2000 {published data only}

Dowsett 1989 {published data only}

Dowsett 1990 {published data only}

Dowsett 1994 {published data only}

Dowsett 1995 {published data only}

Eiermann 2001 {published data only}

Geisler 1996 {published data only}

Geisler 2002 {published data only}

Ingle 1997 {published data only}

Johnston 1994 {published data only}

Miller 1996b {published data only}

Pronzato 1993 {published data only}

Raats 1992 {published data only}

Smith 2005 {published data only}

Svenstrup 1994 {published data only}

Wang 2003 {published data only}

Referencias de los estudios en curso

CAAN {published data only}

ECOG E4101 {published data only}

ICR‐CTSU Sofea {published data only}

Paridaens 2003 {published data only}

Referencias adicionales

Beatson 1896

EBCTCG 2005

Ferlay 2000 [Computer program]

Gibson 2007

Hayward 1977

Higgins 2003