Clinics of Oncology

Systematic Review ISSN: 2640-1037 Volume 7

Systematic Review and Meta-Analysis of the Association between β-Blocker Use and
Survival in Ovarian Cancer Patients
Couttenier Alexandra*, Danwang Celestin and Robert Annie
1
Université catholique de Louvain, Institut de recherche expérimentale et clinique, Pôle d’épidémiologie et de biostatistique, Brussels,
Belgium

*
Corresponding author: Received: 26 Feb 2024 Copyright:
Couttenier Alexandra, Accepted: 06 Apr 2024 ©2024 Couttenier Alexandra. This is an open access arti-
Universite catholique de Louvain (UCL), Institut Published: 12 Apr 2024 cle distributed under the terms of the Creative Commons
de recherche expérimentale et clinique (IREC), J Short Name: COO Attribution License, which permits unrestricted use, distri-
Epidémiologie and Biostatistiques (EPID), Clos bution, and build upon your work non-commercially.
Chapelle- aux-champs, 30 bte B1.30.13, 1200
Brussels, Belgium. Citation:
Couttenier Alexandra, Systematic Review and Meta-Anal-
ysis of the Association Between β-Blocker Use and Sur-
vival in Ovarian Cancer Patients . Clin Onco.
2024; 7(10): 1-13
Abbreviations:
ADJ: Adjuvant; Dx; Diagnosis; Chemo; Chemotherapy; CSS: Cancer Specific Survival; ITB: Immortal Time Bias; EOC: Epithelial Ovarian Cancer; Fu; Follow-Up; Mo;
Month(s); Neo-Ddj; Neo-Adjuvant; NR: Not Reported; OC: Ovarian Cancer; OCSS: Ovarian Cancer Specific Survival; OS: Overall Survival; PFS: Progression
Survival; RFS: Recurrence free Survival; Rx; Prescription; YR; year(s).

1. Abstract 1.4. Conclusion: This meta-analysis did not show an association

1.1. Objectives: β-blockers are drugs frequently prescribed for between β-blocker use and survival of women with OC.
various indications in cardiology and for which anticancer prop- 2. Introduction
erties have been suggested. We aimed to evaluate the association Worldwide, the incidence of ovarian cancer (OC) is estimated
between the use of β-blockers and survival of women with OC. around 6/100 000 women per year [1]. In spite of improvements
1.2. Methods: A systematic literature search of relevant data- in cancer treatments, the prognosis of OC remains poor with a sur-
bases through September 2020 was conducted to identify studies vival rate of about 40% at 5 years [2-4]. In consequence, there
assessing the association between β-blockers use and prognostic is a need for further research aimed at increasing the survival of
in women with OC. The inverse variance weighting method with women diagnosed with OC.
random-effects model was used to calculate pooled hazard ratios β-blockers are the eight most commonly prescribed drugs among
(HR) and 95% confidence intervals (95% CI). We assessed the risk residents of nursing home in Belgium [5]. β-blockers are used for
of immortal time bias (ITB) and the quality of the studies with the various indications including hypertension, cardio protection after
Newcastle–Ottawa scale. Subanalyses were performed based on myocardial infarction and migraine. The variety of these indica-
quality scores and the risk for ITB. tions reflects the abundance of β-adrenoceptors in the body [6,7].
1.3. Results: We identified 23 studies that assessed the impact of Preclinical studies have shown that OC cells express β-adreno-
β-blocker use on OC prognosis. There was no evidence of an as- ceptors and that β-blockers may impede carcinogenesis [8-10].
sociation between the use of β-blockers and the survival (over- Following these encouraging findings, observational studies have
all, OC-specific, progression-free or recurrence-free survival) of investigated the association between β-blocker use and OC out-
patients with OC. Results of subanalyses excluding studies with comes and some of their results seemed to be contradictory. Subse-
potential ITB or low-quality scores didn’t change results. quently, those findings have been summarized in four meta-analy-

clinicsofoncology.com 1
Volume 7 Issue 10 -2024 Systematic Review

ses [11-14]. One of these confirming beliefs that β-blockers might 3.3. Data synthesis and Analysis
improve ovarian cancer survival [11]. And others, conversely, We used the inverse variance weighting method and random-ef-
showing no effect and suggesting that the observed results in fects models to calculate the pooled HRs. When the confidence
some studies were influenced by immortal person-time bias (ITB) limits were not indicated, we estimated variance from the p-values
[12-14]. This bias occurs when the definition of the exposure is (p) [17]. The primary meta-analysis included all studies classified
based on an exposition after the start of the follow-up. By defini- according to survival outcomes measures (overall, ovarian can-
tion, patients had to survive until this exposition to be classified cer-specific, progression-free or recurrence-free survival). When
as exposed. Therefore, exposed patients could not die during this several HRs were reported for different timing of β-blocker use
period, called the immortal time period. The exposed patients were (perioperative, pre- or post-diagnostic use), we used HRs for post-
not yet exposed during this period but they are already classified diagnostic use. Subgroup analyses were also conducted according
as exposed which may lead to an overestimation of survival in the timing of β-blocker use. Further secondary analyses including
this group [15]. We have conducted a systematic review with the only studies considered to be ITB-free were conducted in order to
latest publications to assess the relationship between the use of assess the effect of ITB on the pooled results. I2 statistics was used
β-blockers and OC survival with particular attention to quality of as an index of between- study heterogeneity. The risk of bias of the
the studies and more particularly the risk of ITB. included studies, was rated using the Newcastle–Ottawa quality
3. Methods assessment scale for cohort studies [18]. This scale assesses the
The present systematic review and meta- analysis is reported ac- quality of the following parameters: selection, comparability, and
cording to the Meta- analysis of Observational Studies in Epidemi- exposure/outcome assessment. The presence of potential publica-
ology (MOOSE) guidelines [16]. tion bias was assessed using Egger's test [19]. All analyses were
conducted in RStudio Team (2021).
3.1. Search strategy and selection criteria We performed a sys-
tematic literature search by using the databases of PubMed (Na- 4. Results
tional Library of Medicine), Scopus, and Embase (Elsevier) from 4.1. Study selection
inception through September 2020. The following search terms The selection of studies is shown on Figure 1. Seven hundred nine-
were used: “adrenergic beta-antagonists” and “ovarian neoplasm” teen citations were identified after database searches. Titles of 541
(as Medical Subject Headings terms), and “beta-blocker*” and publications were screened after removing duplicates. Abstracts
“ovar*” and “cancer*”/“tumor*”/“tumour*”/“malignan*” /“neo- or full texts of 95 publications were further reviewed. Finally, 23
plasm*” (as text words in the title or abstract). We made no restric- studies were included in the pooled analyses.
tions on language and publication type. Moreover, we conducted a
manual screen of the reference lists of the retrieved articles, meta-
analysesandreviews. The population considered for this review
was women diagnosed with invasive OC and the exposure of in-
terest was β-blocker use. Outcomes analysed were overall death,
death due to OC, progression and recurrence of OC. Prospective
and retrospective cohort studies reporting hazard ratios (HR) were
selected. Reviews papers, meta-analyses, editorials, letters, com-
mentaries and preclinical studies were excluded.
3.2. Data extraction and Management
We used Endnote X9 to compile the identified studies and remove
the duplicate records. First, we screened the titles for eligibility
and excluded studies with obviously ineligible subjects. Then, we
retrieved and screened the abstracts and full texts of the remaining
studies for final inclusion. When several studies were based on the
same database, we selected the most recent publication with most
complete data. We extracted the following information from each
included publication: the last name of the first author, the study
design, the country, the year of publication, the sample size, the Figure 1. Flow diagram of study inclusion for the meta-analysis.
number of β-blocker users, the follow- up period, the mean or me-
dian age, the adjustment variables, the outcomes, and the HRs with
corresponding 95% confidence intervals (95% CI).

clinicsofoncology.com 2
Volume 7 Issue 10 -2024 Systematic Review

4.2. Characteristics of Included Studies [23], [26], [31], [33], [34], [39]. Studies included were conducted
The characteristics of studies included in the meta-analysis are in USA [21-23], [30-36], [39], [41], Belgium [29], [42], UK [24],
shown in Table 1. Among the 23 included studies, there were 4 [27], Germany [20], [38], Korea [28], [40], Ireland [26], Denmark
cohort studies [20]–[23], 7 population-based studies [24-30] and [25], and Israel [37]. Study quality scores are summarized in Ta-
12 clinical series [31-42]. Fourteen studies were rated as no IT ble 2. The Newcastle–Ottawa scale values ranged from six to nine
biased [22], [24-27], [29-31], [34,36], [38,39], [41,42], 8 were rat- stars: one study was awarded 6 stars [20], 4 study were awarded 7
ed as potentially IT biased [20], [21], [28], [32], [33], [35], [37], stars [6], [13], [16], [18], 9 studies were awarded 8 stars [23-25],
[40] and one presented some analyses with low risk of ITB. Others [27], [32], [35], [37], [40], and 9 studies were awarded 9 stars [22],
had a high risk of ITB [8]. All studies were published between [26], [29], [30], [34], [36], [38], [41], [42]. There was no evidence
2011 and 2021 and 7 were only published in abstract form [21], of publication bias (Egger's test P=0.06).
Table 1. Characteristics of studies included in the meta-analysis by year.

BB BB Patients
Author, ref, Participants BB data Adjusted Potential
Design exposure N (n of Follow-up Outcomes
year, country characteristics source for* ITB
definition users)
subtype

Population Start: dx 1, 2, 8d,

Primary SBB, Pre-dx use: ≥2 rx in
Shah [24], 2011, UK OC 148 (72) Min 1 yr, max OS No
-based study care database NSBB the yr before dx 8e, 10e,
10 yr
12

7 5 % Post-dx use: ≥ 2
1, 3, 4,
SBB, medical documents
Diaz [32], 2012, USA Clinical series Stages III-IV EOC Medical records 248 (23) Start: dx OS Yes
min 6 mo apart after
dx
2 5 %
6a
NSBB

Pre-dx use: ≥ 30
Eskander [31],
days of
Clinical series All stages EOC Medical records nr 680 (144) Start: dx OS 1, 3 No

2012, USA use before dx

Johannesdottir [25],
Population Start: dx 1, 2, 9d,
2013,

Prescription Pre-dx use: 1 rx in 6 6 2 6

All stages OC / OS No
Denmark -based study database 90 days before dx (460) 10bcd

Median: 2.55
yr

8 4 % Post-dx use: ever S t a r t :

Heitz [20], 2013, Self-disclosure 1, 6b, 9e,
SBB, use randomization

Cohort study Recurrent OC 381 (38) OS, PFS Yes

1 6 % (analyzed before each
Germany and explicit request 13
NSBB chemo cycle)

   Median:
17 mo

Beeghly-Fadiel [33], S B B , 1 1 4 7 1, 2, 3, 5,
Clinical series Stages I-IV OC Medical records nr Start: dx OS Yes
2014, USA NSBB (142)

clinicsofoncology.com 3
Volume 7 Issue 10 -2024 Systematic Review

Dickson [34], Perioperative use:

Clinical series All stages OC / / use at time of initial 185 (70) Start: surgery OS, PFS 1, 3, No
surgery

2014, USA

Pre-dx use: use in

Brown [26], Population Start: dx 1, 2, 3, 4,
the yr before dx

Community
1823
Invasive OC prescription / OS OCSS No
records Post-dx: ever use (432) 6a, 8bce,
2015, Ireland -based study
after dx 12

Median: 5.8 yr

All stages OC
with min 2 rx of
Springate [27], Population 1, 2, 8fg,
antihypertensi ve National primary S B B , Pre-dx use: 1 rx in Start: dx Max:
drugs in the 351(151) OS No
care databases NSBB the yr before dx 10 yr

2015, UK -based study yr before dx 10e, 12

72%
Watkins [35], 1, 3, 5,
SBB,
Post-dx use: rx
1425
Clinical series All stages EOC Medical reports 28% during neo- adj or Start: dx OS, OCSS Yes
2015, USA (269) 6ab, 7,
NSBB adj chemo

9ab, 11

Table 1. (Continued).

Participants BB BB exposure Patients N Follow- Adjusted Potential

Author, ref, year, country Design BB data source Outcomes
characteristics definition (n of users) up for* ITB
subtype
S t a r t :
Perioperative
Al-Niaimi [36], primary 1, 3, 4,
use: use at
Clinical series All stages EOC Medical records SBB 185 (70) surgery OS, PFS No
time of initial
surgery Median:
2016, USA 6a, 9a, 11
91 mo

Bar [37], 2016, 143 Start: dx 1, 3, 6b,

Post-dx use:
Healthcare
Israel Clinical series All stages EOC nr min 1 yr of use -25 OS, RFS 9ab, 10abc Yes
pharmacy records
following dx
Median:
48.75 mo

Merritt [21],
Cohort study All stages EOC Questionnaires nr nr nr nr OCSS nr Yes
2016, USA

Heitz [38], 2017, Perioperative 1, 3, 5,

Start: dx.
use: use at
Clinical series All stages EOC Medical records SBB 801 (141) M e d i a n : OS, PFS No
time of initial
40 mo
surgery
Germany 6a, 9cde, 11

clinicsofoncology.com 4
Volume 7 Issue 10 -2024 Systematic Review

Minlikeeva [22],
Questionnaires,
Stages II-IV S B B ,
Cohort study interviews or nr 2294 (318) Start: dx OS, PFS 1, 3 No
2017, USA + EOC NSBB
medical records

Australia
5 1 %
Baek [28], 2018, Population Start: dx 1, 2, 9d,
SBB,
National Health
7 3 %
Korea -based study OC Insurance nr 866 (206) OS, OCSS 10bcd Yes
NSBB
databases
Median:
6.15 yr

(Pre-dx: 899,
Huang [23], 1, 3,4,5,
post-
Cohort study OC nr nr nr Min 4 yr OCSS Yes/ No
2018, USA dx: 683) 11

Perioperative
Mattappally [39], 2018, S B B , use: use at
Clinical series EOC Medical records nr nr OS, PFS nr No
USA NSBB time of initial
surgery

Start: 6
8 0 %
Couttenier [29], 6197 mo after 1, 2, 3, 5,
SBB,
dx
Post-dx use:
Population Healthcare
All stages EOC 3 2 % ever use after OS, OCSS No
2019, Belgium based- study pharmacy records -2373 6ab, 9a
NSBB dx

Median:
3.49 yr

Harding [30], > 66 yr EOC Start: 1 yr

Post-dx use: 2195 1, 2, 3, 5,
Population Healthcare S B B , after dx
≥ 2 rx in the OCSS No
based- study pharmacy records NSBB Mean: 2.2 6ab, 7, 8a,
2019, USA patients yr after dx -1302 yr 8bd, 9abd
Table 1. (Continued)

Participants BB BB exposure Patients N (n F o l l o w - Adjusted Potential

Author, ref, year, country Design BB data source Outcomes
characteristics definition of users) up for* ITB
subtype

4 5 % Post-dx use:
Cho [40], 2020, 1, 3, 6a,
SBB, 1 rx for 6 mo Start:
Clinical series All stages EOC Medical records 878 (62) PFS Yes
following dx surgery
or surgery
5 5 %
Korea 9, 14
NSBB

9 0 % Start:
Gonzalez [41], 1, 3, 6ab,
SBB, surgery
Perioperative:
Stages IIIc-IV
2020, USA Clinical series Medical records 1 0 % use at time of 534 (105) OS 7, 9d, No
EOC NSBB initial surgery
Median:
10abc
49 mo

Couttenier [42], Perioperative: 1, 2, 4, 6,

S B B , Start:
Clinical series All stages EOC Medical records use at time of 170(35) OS No
NSBB surgery
initial surgery
2021, Belgium 9ef, 11

clinicsofoncology.com 5
Volume 7 Issue 10 -2024 Systematic Review

Abbreviations: adj, adjuvant; dx, diagnosis; chemo, chemotherapy; CSS, cancer specific survival; ITB, immortal time bias; EOC, epithelial ovarian cancer; fu, follow-up;
mo, month(s); neo-adj, neo-adjuvant; nr, not reported; OC, ovarian cancer; OCSS, ovarian cancer specific survival; OS, overall survival; PFS, progression sur-
vival; RFS, recurrence free survival; rx, prescription; yr, year(s).
*1, Age at diagnosis; 2, year of diagnosis; 3, stage; 4, grade; 5, tumour histology; 6 cancer treatment (6a, surgery/ cytoreductive status/ residual tumour; 6b, chemother-
apy); 7, race/ethnicity; 8, socio-economic variable (8a, census tract poverty level; 8b, marital status; 8c, urban/rural; 8d, national region/location of residence; 8e, area
deprivation; 8f, Regional Health Authority and practice postcode; 8g Index of Multiple Deprivation. ); 9, comorbidities (9a, diabetes mellitus; 9b hypertension; 9c,
American Society of Anesthesiologist (ASA) class; 9d, Charlson score; 9e, ECOG performance status/ WHO status; 9f, cardiovascular disease); 10, concomitant
drug use (10a, metformin; 10b, statin; 10c, aspirin; 10d, diuretic; 10e, number of medications received in the year before diagnosis); 11, BMI; 12, smoking;
13, study treatment; 14, BRCA mutation.
Table 2. Methodological quality of studies included in the meta-analysis.

Selection Comparability Outcome

Selection of Outcome of Follow‐up long

Author, ref Representativen Control for Adequacy of
the Ascertainment of interest not Assessment enough
ess of the important factor follow‐up
unexposed exposure present at start of outcome for outcomes
exposed cohort or additional factora of cohorts
cohort of study to occurb

Shah [24] * * * * * * * *

Diaz [32] * * * * * * * *
Eskander [31] * * * * ** * *

Johannesdottir [25] * * * * * * * *

Heitz [20] * * * * * *

Beeghly-Fadiel [33] * * * * * * *

Dickson [34] * * * * ** * * *
Brown [26] * * * * ** * * *
Springate [27] * * * * * * * *
Watkins [35] * * * * * * * *
Al-Niaimi [36] * * * * ** * * *
Bar [37] * * * * * * * *
Merritt [21] * * * * * * *
Heitz [38] * * * * ** * * *
Minlikeeva [22] * * * * ** * * *
Baek [28] * * * * * * *
Huang [23] * * * * * * * *

Mattappally [39] * * * * * * *

Couttenier [29] * * * * ** * * *
Harding [30] * * * * ** * * *
Cho [40] * * * * * * * *
Gonzalez [41] * * * * ** * * *
Couttenier [42] * * * * ** * * *

Studies could be awarded a maximum of one star for each item except for the item Control for important factor or additional factor. The explanation of each column
of the Newcastle-Ottawa Scale is available from [18]. a Studies received one star for controlling each of these factors: immortal time bias and stage. (A maximum of
two stars could be awarded for this item.) b Studies with a median follow-up time ≥ 24 months were assigned one star. c Studies with a follow-up rate > 75% were
assigned one star.

clinicsofoncology.com 6
Volume 7 Issue 10 -2024 Systematic Review

4.3. Overall Survival estimate of a secondary analysis excluding studies with potential risk
Nineteen studies investigated the association between β-blocker use for ITB (Figure 3) showed no OS benefit for β-blockers users(HR,1.09;
and overall survival (OS). Among these, 13 studies (7 clinical series 95%CI,0.96-1.2;I2,57.9%). In order to explore between-study het-
and 5 population-based studies and 1 cohort study) were rated as erogeneity, we performed subanalyses based on timing of exposure
ITB-free and the six remaining were likely to have ITB. The pooled (Figures S1, S2 and S3), quality scores (Figure S4), and one exclud-
HR for β-blocker use and OS was 0.85 (95% CI, 0.69-1.03) with be- ing the study of Mattappally et al. [39] which reports results very differ-
tween-study heterogeneity (I2, 61.1%; p, <0.01) (Figure 2). The pooled ent from those of other studies (Figure S5).

Figure 2: Forest plot (random-effects model) of β-blockers use and overall survival. HR, hazard ratio; ITB, immortal time bias; N, number of
patients; OS, overall survival; 95% CI, 95% confidence interval.

Figure 3: Forest plot (random-effects model) of β-blockers use and overall survival, restricted to studies with low risk of immortal time bias.
HR, hazard ratio; ITB, immortal time bias; N, number of patients; OS, overall survival; 95% CI, 95% confidence interval.

Figure S1. Forest plot (random-effects model) of β-blockers pre-diagnostic use and overall survival.

HR, hazard ratio; ITB, immortal time bias; N, number of patients; OS, overall survival; 95% CI, 95% confidence interval.

clinicsofoncology.com 7
Volume 7 Issue 10 -2024 Systematic Review

Figure S2. Forest plot (random-effects model) of β-blockers perioperative use and overall survival.

HR, hazard ratio; ITB, immortal time bias; N, number of patients; OS, overall survival; 95% CI, 95%
confidence interval.

Figure S3. Forest plot (random-effects model) of β-blockers post-diagnostic use and overall survival.

HR, hazard ratio; ITB, immortal time bias; N, number of patients; OS, overall survival; 95% CI, 95%
confidence interval

Figure S4. Forest plot (random-effects model) of β-blockers use and overall survival, restricted to studies with NOS≥8.

HR, hazard ratio; ITB, immortal time bias; N, number of patients; OS, overall survival; 95% CI, 95%
confidence interval.

clinicsofoncology.com 8
Volume 7 Issue 10 -2024 Systematic Review

Figure S5. Forest plot (random-effects model) of β-blockers use and overall survival excluding the study of Mattappally et al [39].

HR, hazard ratio; ITB, immortal time bias; N, number of patients; OS, overall survival; 95% CI, 95% confidence interval.
4.4. Ovarian Cancer Specific Survival significance (HR, 0.73; 95% CI, 0.51- 1.06) with between-study hetero-
Six studies have investigated the association between β-blocker use geneity (I2, 91.5%; p, <0.001) (Figure 4). Conversely, the subanal-
and ovarian cancer specific survival (OCSS). These 6 studies have an- ysis excluding studies with potential ITB showed no association
alysed the post-diagnostic use of β-blockers and among these studies, between β-blockers use and OCSS (HR, 0.95; 95% CI, 0.74-1.23;
3 were rated as having a high risk for ITB. The pooled data suggest- I2, 85.5%) (Figure 5) In order to explore between-study heteroge-
ed a possible improvement of OCSS that didn’t reached the statistical neity, we performed a subanalysis based on quality scores (Figure
S6).

Figure 4. Forest plot (random-effects model) of β-blockers use and ovarian cancer-specific survival. HR, hazard ratio; ITB, immortal time bias; N,
number of patients; OCSS, ovarian cancer-specific survival; 95% CI, 95% confidence interval.

Figure 5. Forest plot (random-effects model) of β-blockers use and ovarian cancer-specific survival, restricted to studies with low risk of im-
mortal time bias. HR, hazard ratio; ITB, immortal time bias; N, number of patients; OCSS, ovarian cancer-specific survival; 95% CI, 95% confidence interval.

clinicsofoncology.com 9
Volume 7 Issue 10 -2024 Systematic Review

Figure 6. Forest plot (random-effects model) of β-blockers use and progression-free survival. HR, hazard ratio; ITB, immortal time bias; N, number
of patients; PFS, progression-free survival; 95% CI, 95% confidence interval.

Figure 7. Forest plot (random-effects model) of β-blockers use and progression-free survival, restricted to studies with low risk of immortal
time bias. HR, hazard ratio; ITB, immortal time bias; N, number of patients; PFS, progression-free survival; 95% CI, 95% confidence interval.

Figure S6. Forest plot (random-effects model) of β-blockers use and ovarian cancer-specific survival, restricted to studies with NOS≥8.

HR, hazard ratio; ITB, immortal time bias; N, number of patients; OCSS, ovarian cancer-specific survival; 95% CI, 95% confidence interval.

Figure S7. Forest plot (random-effects model) of β-blockers perioperative use and progression-free survival.

HR, hazard ratio; ITB, immortal time bias; N, number of patients; PFS, progression-free survival; 95% CI, 95% confidence
interval.

clinicsofoncology.com 10
Volume 7 Issue 10 -2024 Systematic Review

Figure S8. Forest plot (random-effects model) of β-blockers post-diagnostic use and progression-free survival.

HR, hazard ratio; ITB, immortal time bias; N, number of patients; PFS, progression-free survival; 95% CI, 95% confidence interval.

Figure S9. Forest plot (random-effects model) of β-blockers perioperative use and progression-free survival, restricted to studies with NOS≥8.

HR, hazard ratio; ITB, immortal time bias; N, number of patients; PFS, progression-free survival; 95% CI, 95% confidence interval.
5. Discussion study also presents some limitations. Firstly, we have no information
In this systematic review and meta-analysis of twenty-three non-ran- regarding the compliance to the use of β-blocker. Secondly, we cannot
domized studies, there was no significant association between β- exclude the risk of information bias in the included studies. Thirdly, we
blocker use and OC prognosis. The pooled estimates were essentially cannot rule out the risk of residual confounding from unregistered
similar for OS, OCSS, PFS and for all secondary analysis based on variables. Nevertheless, the present systematic review and meta-anal-
time of exposure, risk of ITB or NOS. The biological mechanisms by ysis showed no beneficial effect of β-blocker use on OC prognosis. All
which β-blockers might improve the prognosis of women with OC studies showed that women keeping a β-blocker treatment after an
have been investigated in previous in vitro and in vivo studies [8-10]. OC diagnosis of didn’t have a poorer prognosis than women who didn’t
Preclinical studies have shown that adrenergic receptors-β (ADRB) use β-blockers.
are expressed on OC cells. When catecholamine hormones bind these
References
receptors (more specifically ADRB2) it activates the protein kinase
A signaling pathway which stimulates the expression of vascular 1. J Ferlay. Cancer incidence and mortality worldwide: Sources, meth-
endothelial growth factor (VEGF) and increases the production of ma- ods and major patterns in GLOBOCAN 2012: Globocan 2012 », Int
trix metalloproteinase (MMP)-2 and MMP-9. VEGF enhances the J. 2015; 136: E359 E386.
formation of blood vessels and MMPs are involved in cell prolif- 2. JD Wright. Trends in Relative Survival for Ovarian Cancer from
eration, differentiation, migration, angiogenesis and apoptosis [8,9]. 1975 to 2011 », Obstet. Gynecol. 2015; 125: 1345 1352.
Experimental studies have suggested that these pro-tumoral effects 3. B Trétarre. Ovarian cancer in France: Trends in incidence, mortality
could be abrogated by β-blockers [8]. Our meta-analysis has numer- and survival, 1980–2012 », Gynecol Oncol.2015; 139: 324 329.
ous strengths. First, our literature search was comprehensive, system- 4. L A Baldwin. Ten-Year Relative Survival for Epithelial Ovarian Can-
atic, reproducible and included published and unpublished pa- cer »:, Obstet. Gynecol. 2012; 120: 612-618.
pers. None exclusion criteria in terms of language, methodological 5. PMS Anrys, GC Strauven, V Foulon, JM Degryse, S Henrard.
characteristics or place of publication were applied. Compared to Spinewine, « Potentially Inappropriate Prescribing in Belgian Nurs-
the most recent meta-analyses conducted by Wen et al. [43] our analysis ing Homes: Prevalence and Associated Factors », J Am Med Dir.
included 12 additional studies. Second, we carefully assessed meth- 2018; 19: 884 890.
odological quality and risk of ITB in all studies. We performed sec- 6. HT Ong. « β blockers in hypertension and cardiovascular disease »,
ondary analyses excluding studies with lower NOS or serious risk of BMJ, vol. 2007; 334: 946 949.
ITB. Moreover, the results of all our subanalyses weresimilar. Our
clinicsofoncology.com 11
Volume 7 Issue 10 -2024 Systematic Review

7. MR Bristow, « Mechanism of Action of Beta-Blocking Agents in Findings from a population- based retrospective cohort study: β- ad-
Heart Failure », Am J Cardiol. 1997; 80: 26L-40L. renoceptor blockers and cancer survival », Br. J. Clin. Pharmacol.,
8. PH Thaker. « Chronic stress promotes tumor growth and angiogen- vol. 2011; 72: 157‑161.
esis in a mouse model of ovarian carcinoma », Nat. Med. 2006; 939 25. SA Johannesdottir. « Use of ß- blockers and mortality following
944. ovarian cancer diagnosis: a population-based cohort study », BMC
9. SK Lutgendorf. Stress-related mediators stimulate vascular endothe- Cancer, vol. 2013; 13: 85.
lial growth factor secretion by two ovarian cancer cell lines », Clin. 26. C Brown, TI Barron, K Bennett, L Sharp, « Associations between
Cancer Res. Off. J Am Assoc Cancer Res. 2003; 9: 4514 4521. pre- and post- diagnostic use of beta-blockers and ovarian cancer
10. MMK Shahzad. « Stress effects on FosB and interleukin-8 survival », p. 1378827 Bytes. 2015.
(IL8)-driven ovarian cancer growth and metastasis. », J. Biol Chem 27. DA Springate, DM Ashcroft, E Kontopantelis, T Doran, R Ryan. D
vol. 2018; 293: 10041. Reeves, « Can analyses of electronic patient records be independent-
11. CH Choi. « Meta-analysis of the effects of beta blocker on survival ly and externally validated? Study 2--the effect of - adrenoceptor
time in cancer patients », J. Cancer Res. Clin. Oncol. 2014; 140: blocker therapy on cancer survival: a retrospective cohort study »,
1179‑1188. BMJ Open, vol. 2015; e007299‑e007299. avr. 2015.

12. Z Na. « The effects of beta-blocker use on cancer prognosis: a me- 28. MH Baek, DY Kim, SO Kim, YJ Kim, YH Park, « Impact of beta
ta-analysis based on 319,006 patients », OncoTargets Ther. vol. blockers on survival outcomes in ovarian cancer: a nationwide pop-
2018; 11: 4913‑4944. ulation-based cohort study ». J Gynecol Oncol. vol. 2018; 29: e82.

13. A Yap « Effect of beta-blockers on cancer recurrence and survival: a 29. A Couttenier, O Lacroix, G Silversmit, E Vaes, H De Schutter, A
meta- analysis of epidemiological and perioperative studies », Br. J. Robert, « Beta- blocker use and mortality following ovarian cancer
Anaesth. 2018; 121: 45‑57. diagnosis: a population-based study», Cancer Epidemiol. vol. 2019;
62: 101579.
14. A Majidi, R Na, S Dixon-Suen, SJ Jordan. P M Webb, « Common
medications and survival in women with ovarian cancer: A systemat-
ic review and meta-analysis », Gynecol. Oncol. 2020; 157: 678‑685. 30. BN Harding, JA Delaney, RR Urban, NS Weiss, « Post-diagnosis use
15. S Suissa, « Immortal Time Bias in Pharmacoepidemiology », Am J of antihypertensive medications and the risk of death from ovarian
Epidemiol. vol. 2008; 167: 492‑499. cancer », Gynecol Oncol. vol. 2019; 154: 426‑431.

16. D F Stroup. « Meta-analysis of Observational Studies in Epidemiol- 31. R Eskander. « Beta blocker use and ovarian cancer survival: A retro-
ogyA Proposal for Reporting », JAMA, vol. 2008; 283: 2008. spective cohort study », Gynecol. Oncol. vol. 2012; 127: S21.

17. DG Altman. M. Bland, « How to obtain the confidence interval from 32. E S Diaz, B Y Karlan, AJ Li. « Impact of beta blockers on epithelial
a P value », BMJ, vol. 2011; 343: 2090‑d2090. ovarian cancer survival », Gynecol Oncol. vol. 2012; 127: 375‑378.

18. Ottawa Hospital Research Institute ». http://www.ohri.ca/programs/ 33. A Beeghly-Fadiel. « Beta-Blocker Use and Ovarian Cancer Survival
clinical_epide miology/oxford.asp (consulté le 22 septembre. 2021). as Determined by Electronic Medical Records », J. Womens Health,
vol. 2014; 23: 852‑852.
19. JPA Ioannidis, NA Patsopoulos, E Evangelou. « Uncertainty in
heterogeneity estimates in meta-analyses », BMJ, vol. 2007; 335: 34. EL Dickson, J Karnowski, S Saha, C, Albertin A, McNally, AN
914‑916. Al-Niaimi, « Perioperative β blockade improves overall survival in
patients with ovarian cancer », Gynecol Oncol. vol. 2015; 137: 106.
20. F Heitz. « Impact of beta blocker medication in patients with plat-
inum sensitive recurrent ovarian cancer—a combined analysis of 2 35. JL Watkins. « Clinical impact of selective and nonselective be-
prospective multicenter trials by the AGO Study Group, NCIC-CTG ta-blockers on survival in patients with ovarian cancer: Be-
and EORTC-GCG », Gynecol. Oncol. vol. 2013; 129: 463‑466. ta-Blockers and Ovarian Cancer Survival », Cancer vol. 2015; 121:
3444‑3451.
21. MA Merritt, MS Rice, SS Tworoger. EM Poole. « Abstract AP07:
USE OF COMMON MEDICATIONS AND SURVIVAL AFTER 36. A Al-Niaimi. « The impact of perioperative β blocker use on patient
OVARIAN CANCER DIAGNOSIS », in Detection and Prevention outcomes after primary cytoreductive surgery in high-grade epithe-
of Ovarian Cancer, juin. 2017; AP07‑AP07. lial ovarian carcinoma », Gynecol Oncol. vol. 2016; 143: 521‑525.

22. AN Minlikeeva. « History of hypertension, heart disease, and dia- 37. D Bar, O Lavie, N Stein, I Feferkorn, A Shai. « The effect of meta-
betes and ovarian cancer patient survival: evidence from the ovarian bolic comorbidities and commonly used drugs on the prognosis of
cancer association consortium », Cancer Causes Control, vol. 2017; patients with ovarian cancer », Eur J Obstet Gynecol Reprod Biol.
28: 469‑486. vol. 2016; 207: 227‑231.

23. T Huang, AK Sood, SS Tworoger. « Abstract 4252: Antihypertensive 38. F Heitz. « Intake of selective beta blockers has no impact on surviv-
medication use and ovarian cancer survival », in Epidemiology, juill. al in patients with epithelial ovarian cancer », Gynecol Oncol. vol.
2018; 4252‑4252. 2017; 144: 181‑186.

24. SM Shah, IM Carey, CG Owen, T Harris, S DeWilde, DG Cook. 39. N Mattappally, S Korets, S Hughes, S Zweizig, L Bradford. « Effect
« Does β- adrenoceptor blocker therapy improve cancer survival? of Peri- Operative Selective and Nonselective Beta Blocker Use on
clinicsofoncology.com 12
Volume 7 Issue 10 -2024 Systematic Review

Survival in Ovarian Cancer Patients [20A] », Obstet Gynecol. vol.

2018; 131: 14S-14S.
40. MA Cho. « Impact of Angiotensin Receptor Blockers, Beta Block-
ers, Calcium Channel Blockers and Thiazide Diuretics on Surviv-
al of Ovarian Cancer Patients », Cancer Res Treat. vol. 2020; 52:
645‑654.
41. R Gonzalez. «Multivariable analysis of association of beta-blocker
use and survival in advanced ovarian cancer », Gynecol Oncol. vol.
2020; 157: 700‑705.
42. Alexandra Couttenier, Olivia Lacroix, Martine Berlière, Jean-Pas-
cal Machiels, Annie Robert, « Statin and β-blocker use in ovarian
cancer patients: a Belgian clinical series ».
43. ZY Wen. « Post-Diagnostic Beta Blocker Use and Prognosis of
Ovarian Cancer: A Systematic Review and Meta- Analysis of 11
Cohort Studies with 20,274 Patients », Front Oncol. vol. 2021; 11:
665617.

clinicsofoncology.com 13