Fulvestrant for hormone‐sensitive metastatic breast cancer

Clara I Lee; Annabel Goodwin; Nicholas Wilcken

doi:10.1002/14651858.CD011093.pub2

Cochrane Database of Systematic Reviews

Fulvestrant for hormone‐sensitive metastatic breast cancer

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DOI:

https://doi.org/10.1002/14651858.CD011093.pub2 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

03 enero 2017see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Cáncer de mama

Copyright:

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Clara I Lee

Correspondencia a: Medical Oncology, Westmead Hospital, Westmead, Australia

[email protected]

Sydney Medical School, The University of Sydney, Sydney, Australia
Annabel Goodwin

Concord Clinical School, The University of Sydney, Concord Repatriation General Hospital, Concord, Australia

Medical Oncology Department, Concord Repatriation General Hospital, Concord, Australia

Cancer Genetics Department, Sydney Local Health District and South Western Sydney Local Health District, Sydney, Australia
Nicholas Wilcken

Medical Oncology, Westmead Hospital, Westmead, Australia

Sydney Medical School, The University of Sydney, Sydney, Australia

Contributions of authors

Clara Lee (CL): screened studies for eligibility, extracted and analysed data, and wrote the review.
Annabel Goodwin (AG): cowrote the second version of the protocol and provided comments, oversight, and feedback on the full review.
Nicholas Wilcken (NW): cowrote the second version of the protocol, screened studies for eligibility, provided oversight for the review, and wrote the review.

Sources of support

Internal sources

None, Other.

External sources

None, Other.

Declarations of interest

CL: None to disclose associated with this review. Other, unrelated funding has been received from Novartis, Sanofi, Ipsen, Amgen, Roche (conference support) and honoraria from Roche.
AG: Roche virtual ASCO 2015 and 2016 subscriptions. Advisory board for Novartis 2015.
NW: Honoraria from Roche. On advisory boards for Novartis, Pfizer, Roche.

Acknowledgements

We wish to acknowledge the advice received from Dianne O'Connell and Jessica Barrett. We also acknowledge the authors that were involved in the first draft of this protocol and are not involved in further developments of the protocol and review stage: E Amir, J Beyene, P Shah, and H Chen. We acknowledge Orit Freedman and Mark Clemons for their contribution during the protocol phase of our review. We also thank Melina Willson for her invaluable contribution and guidance in the processes and conduct of this review.

Version history

Published

Title

Stage

Authors

Version

2017 Jan 03

Fulvestrant for hormone‐sensitive metastatic breast cancer

Review

Clara I Lee, Annabel Goodwin, Nicholas Wilcken

https://doi.org/10.1002/14651858.CD011093.pub2

2014 May 01

Fulvestrant for hormone‐sensitive metastatic breast cancer

Protocol

Clara I Lee, Annabel Goodwin, Orit Freedman, Mark Clemons, Nicholas Wilcken

https://doi.org/10.1002/14651858.CD011093

Differences between protocol and review

We revised comparator 2 to "any other standard anticancer agent".

We selected three toxicities for analysis: vasomotor, anthralgia, and gynaecological toxicity based on clinical judgement and prior to review of the results.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Female; Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Forest plot of comparison: 1 Progression‐free survival, outcome: 1.1 Fulvestrant vs other endocrine therapy.

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Figure 4

Forest plot of comparison: 2 Clinical benefit rate, outcome: 2.1 Fulvestrant vs other endocrine therapy.

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Figure 5

Forest plot of comparison: 3 Overall survival, outcome: 3.1 Fulvestrant vs other endocrine therapy.

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Analysis 1.1

Comparison 1 Progression‐free survival, Outcome 1 Fulvestrant vs other endocrine therapy.

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Analysis 1.2

Comparison 1 Progression‐free survival, Outcome 2 First‐line vs second‐line or more.

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Analysis 1.3

Comparison 1 Progression‐free survival, Outcome 3 Combination fulvestrant vs single agent with other endocrine therapy.

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Analysis 2.1

Comparison 2 Clinical benefit rate, Outcome 1 Fulvestrant vs other endocrine therapy.

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Analysis 2.2

Comparison 2 Clinical benefit rate, Outcome 2 Clinical benefit rate (first‐line vs second‐line).

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Analysis 2.3

Comparison 2 Clinical benefit rate, Outcome 3 Combination vs monotherapy fulvestrant.

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Analysis 3.1

Comparison 3 Overall survival, Outcome 1 Fulvestrant vs other endocrine therapy.

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Analysis 4.1

Comparison 4 Toxicity, Outcome 1 Vasomotor.

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Analysis 4.2

Comparison 4 Toxicity, Outcome 2 Arthralgia.

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Analysis 4.3

Comparison 4 Toxicity, Outcome 3 Gynaecological.

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Summary of findings for the main comparison. Fulvestrant versus other endocrine treatment

Fulvestrant versus any other endocrine therapy for hormone‐sensitive advanced breast cancer
Patient or population: women with hormone‐sensitive advanced breast cancer Setting: cancer centre Intervention: fulvestrant Comparison: any other standard endocrine therapy
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with any other standard endocrine therapy	Risk with fulvestrant
Time to progression follow‐up: range 8.9 months to 38 months	Low‐risk population		HR 0.95 (0.89 to 1.02)	4258 (9 RCTs)	⊕⊕⊕⊝ MODERATE ^2,3,4
	500 events per 1000¹	482 events per 1000 (460 to 507)
	High‐risk population
	600 events per 1000¹	581 events per 1000 (558 to 607)
Clinical benefit rate follow‐up: range 8.9 months to 38 months	Study population		RR 1.03 (0.97 to 1.10)	4105 (9 RCTs)	⊕⊕⊕⊕ HIGH ³
	486 per 1000	501 per 1000 (471 to 535)
Mortality follow‐up for overall survival: range 8.9 months to 38 months	Low‐risk population		HR 0.97 (0.87 to 1.09)	2480 (5 RCTs)	⊕⊕⊕⊕ HIGH ^2,3
	350 deaths per 1000⁵	342 deaths per 1000 (313 to 375)
	High‐risk population
	400 deaths per 1000⁵	391 deaths per 1000 (359 to 427)
Vasomotor toxicity follow‐up: range 8.9 months to 38 months	Study population		RR 1.02 (0.89 to 1.18)	3544 (8 RCTs)	⊕⊕⊕⊕ HIGH ²
	170 per 1000	174 per 1000 (151 to 201)
Arthralgia follow‐up: range 8.9 months to 38 months	Study population		RR 0.96 (0.86 to 1.09)	3244 (7 RCTs)	⊕⊕⊕⊕ HIGH ²
	225 per 1000	216 per 1000 (193 to 245)
Gynaecological toxicity follow‐up: range 8.9 months to 38 months	Study population		RR 1.22 (0.94 to 1.57)	2848 (6 RCTs)	⊕⊕⊕⊕ HIGH ^{4 6}
	68 per 1000	83 per 1000 (64 to 107)
Quality of life assessed with: FACT‐B or FACT‐ES questionnaire follow‐up: range 8.9 months to 38 months	None of the studies reported a difference in quality of life between women receiving fulvestrant and other endocrine treatments		‐	(4 RCTs)	⊕⊕⊕⊕ HIGH
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FACT‐B: Functional Assessment of Cancer Therapy‐Breast; FACT‐ES: Functional Assessment of Cancer Therapy‐Endocrine Symptoms; HR: hazard ratio; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹The baseline risk for the control groups was calculated at 12 months for those women at relatively low risk (first‐line treatment) and at 6 months for those women at high risk (after first‐line treatment). ²Although heterogeneity was detected (I² ranged from 55% to 66%), this can be explained by the different doses of fulvestrant (250 mg and 500mg), different comparator drugs, and different lines of treatment. ³Less than 80% of women in both arms in one study, Howell, Fulvestrant vs Tamoxifen 2004, had oestrogen receptor ‐positive tumours. ⁴Eight of the nine studies investigated fulvestrant 250 mg rather than the standard 500 mg dose, the latter which has been demonstrated to be superior in a randomised trial (CONFIRM: Di Leo 2010; Di Leo 2012). ⁵The baseline risk for the control groups was calculated at 24 months for those women at relatively low risk (first‐line treatment) and at 12 months for those women at high risk (after first‐line treatment). ⁶The agent used in the control arm varied across studies; the nature of gynaecological toxicity associated with tamoxifen can differ from that with the aromatase inhibitors.

Summary of findings for the main comparison. Fulvestrant versus other endocrine treatment

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Comparison 1. Progression‐free survival

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Fulvestrant vs other endocrine therapy Show forest plot	9	4258	Hazard Ratio (Fixed, 95% CI)	0.95 [0.89, 1.02]

1.1 Fulvestrant 500 mg vs anastrozole	1	205	Hazard Ratio (Fixed, 95% CI)	0.66 [0.47, 0.93]
1.2 Fulvestrant 250 mg vs anastrozole	5	2293	Hazard Ratio (Fixed, 95% CI)	0.93 [0.85, 1.02]
1.3 Fulvestrant 250 mg vs exemestane	2	1173	Hazard Ratio (Fixed, 95% CI)	0.96 [0.85, 1.08]
1.4 Fulvestrant 250 mg vs tamoxifen	1	587	Hazard Ratio (Fixed, 95% CI)	1.18 [0.98, 1.42]
2 First‐line vs second‐line or more Show forest plot	9	4251	Hazard Ratio (Fixed, 95% CI)	0.94 [0.89, 1.01]

2.1 Firstline	4	1996	Hazard Ratio (Fixed, 95% CI)	0.93 [0.84, 1.03]
2.2 Secondline or more	5	2255	Hazard Ratio (Fixed, 95% CI)	0.96 [0.88, 1.04]
3 Combination fulvestrant vs single agent with other endocrine therapy Show forest plot	9	4251	Hazard Ratio (Fixed, 95% CI)	0.94 [0.89, 1.01]

3.1 Single agent fulvestrant with other endocrine therapy	7	3046	Hazard Ratio (Fixed, 95% CI)	0.97 [0.90, 1.04]
3.2 Combination vs other endocrine therapy	2	1205	Hazard Ratio (Fixed, 95% CI)	0.87 [0.77, 0.99]

Comparison 1. Progression‐free survival

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Comparison 2. Clinical benefit rate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Fulvestrant vs other endocrine therapy Show forest plot	9	4105	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.97, 1.10]

1.1 Fulvestrant 500 mg vs anastrozole	1	205	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.90, 1.30]
1.2 Fulvestrant 250 mg vs anastrozole	5	2293	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.99, 1.14]
1.3 Fulvestrant 250 mg vs exemestane	2	1020	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.90, 1.31]
1.4 Fulvestrant 250 mg vs tamoxifen	1	587	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.76, 1.00]
2 Clinical benefit rate (first‐line vs second‐line) Show forest plot	9	4104	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.96, 1.07]

2.1 Firstline	4	1999	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.94, 1.07]
2.2 Secondline	5	2105	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.92, 1.15]
3 Combination vs monotherapy fulvestrant Show forest plot	9	4104	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.96, 1.07]

3.1 Monotherapy fulvestrant vs other endocrine therapy	7	2896	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.93, 1.09]
3.2 Combination with fulvestrant vs other endocrine therapy	2	1208	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.95, 1.12]

Comparison 2. Clinical benefit rate

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Comparison 3. Overall survival

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Fulvestrant vs other endocrine therapy Show forest plot	5	2480	Hazard Ratio (Fixed, 95% CI)	0.97 [0.87, 1.09]

Comparison 3. Overall survival

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Comparison 4. Toxicity

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vasomotor Show forest plot	8	3544	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.89, 1.18]

1.1 Fulvestrant 500 mg vs anastrozole	1	205	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.46, 1.89]
1.2 Fulvestrant 250 mg vs anastrozole	4	1590	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [1.01, 1.58]
1.3 Fulvestrant 250 mg vs exemestane	2	1168	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.77, 1.19]
1.4 Fulvestrant 250 mg vs tamoxifen	1	581	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.46, 1.00]
2 Arthralgia Show forest plot	7	3244	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.86, 1.09]

2.1 Fulvestrant 500mg vs anastrozole	1	205	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [0.66, 3.03]
2.2 Fulvestrant 250mg vs anastrozole	4	1871	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.86, 1.16]
2.3 Fulvestrant 250mg vs exemestane	2	1168	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.72, 1.07]
3 Gynaecological Show forest plot	6	2848	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.94, 1.57]

3.1 Fulvestrant 500mg vs anastrozole	1	205	Risk Ratio (M‐H, Fixed, 95% CI)	4.04 [0.46, 35.52]
3.2 Fulvestrant 250mg vs anastrozole	3	1585	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.92, 1.66]
3.3 Fulvestrant 250mg vs exemestane	1	477	Risk Ratio (M‐H, Fixed, 95% CI)	2.47 [1.20, 5.08]
3.4 Fulvestrant 250mg vs tamoxifen	1	581	Risk Ratio (M‐H, Fixed, 95% CI)	0.12 [0.03, 0.54]

Comparison 4. Toxicity

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Fulvestrant for hormone‐sensitive metastatic breast cancer

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