British Journal of Anaesthesia, ▪ (▪): 1e13 (2018)

doi: 10.1016/j.bja.2018.03.024
Advance Access Publication Date: xxx
Review Article

REVIEW ARTICLE

Effect of beta-blockers on cancer recurrence and

survival: a meta-analysis of epidemiological and
perioperative studies
A. Yap1,2,*, M. A. Lopez-Olivo3, J. Dubowitz1,4, G. Pratt3, J. Hiller1,5,6,
V. Gottumukkala3, E. Sloan1,4,7, B. Riedel1,4,5 and R. Schier1,8
1
Department of Anaesthesia, Perioperative and Pain Medicine, Peter MacCallum Cancer Centre, Melbourne,
VIC, Australia, 2Department of Anaesthesia and Pain Medicine, Princess Margaret Hospital, Perth, WA,
Australia, 3The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA, 4Drug Discovery
Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC,
Australia, 5Department of Anaesthesia, Pain and Perioperative Medicine Unit, The University of Melbourne,
Parkville, VIC, Australia, 6Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton,
VIC, Australia, 7Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, University
of California Los Angeles, Los Angeles, CA, USA and 8Department of Anaesthesiology and Intensive Care
Medicine, University Hospital of Cologne, Germany

*Corresponding author. E-mail: andreapyap@gmail.com

Abstract
Background: The biological perturbation associated with psychological and surgical stress is implicated in
cancer recurrence. Preclinical evidence suggests that beta-blockers can be protective against cancer progres-
sion. We undertook a meta-analysis of epidemiological and perioperative clinical studies to investigate the
association between beta-blocker use and cancer recurrence (CR), disease-free survival (DFS), and overall
survival (OS).
Methods: Databases were searched until September 2017, reported hazard ratios (HRs) pooled, and 95% confidence
intervals (CIs) calculated. Comparative studies examining the effect of beta-blockers (selective and non-selective)
on cancer outcomes were included. The Newcastle Ottawa Scale was used to assess methodological quality and
bias.
Results: Of the 27 included studies, nine evaluated the incidental use of non-selective beta-blockers, and ten were
perioperative studies. Beta-blocker use had no effect on CR. Within subgroups of cancer, melanoma was associated with
improved DFS (HR 0.03, 95% CI 0.01e0.17) and OS (HR 0.04, 95% CI 0.00e0.38), while endometrial cancer had an associated
reduction in DFS (HR 1.40, 95% CI 1.10e1.80) and OS (HR 1.50, 95% CI 1.12e2.00). There was also reduced OS seen with
head and neck and prostate cancer. Non-selective beta-blocker use was associated with improved DFS and OS in ovarian
cancer, improved DFS in melanoma, but reduced OS in lung cancer. Perioperative studies showed similar variable effects
across cancer types, albeit from a limited data pool.
Conclusion: Beta-blocker use had no evident effect on CR. The beneficial effect of beta-blockers on DFS and OS in the
epidemiological or perioperative setting remains variable, tumour-specific, and of low-level evidence at present.

Editorial decision: March 30, 2018; Accepted: March 30, 2018

© 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
For Permissions, please email: permissions@elsevier.com

1
 2 - Yap et al.
Keywords: beta-blockers; cancer recurrence; disease-free survival; overall survival; perioperative
Editor’s key points

This meta-analysis of clinical studies found that beta-
blocker use had no overall effect on cancer recurrence,
disease-free survival or overall survival in patients
with cancer.

Within cancer subgroups, the beneficial effect of beta-
blockers remains variable and of low-level evidence at
present. Improved survival was seen in melanoma and
ovarian cancer, but decreased survival in endometrial,
head and neck, prostate, and lung cancer.
Beta-adrenergic receptor antagonists (beta-blockers) have
been used since the 1960s for the treatment of hypertension,
ischaemic heart disease, and anxiety disorders.1 Recent pre-
clinical evidence suggests that beta-blockers may have a
protective effect against cancer progression. Beta-
adrenoceptors (bAR)2 are present on cancer and immune
cells3 and bAR signalling accelerates cancer spread.4 In vivo
studies have shown that b-blocker treatment may prevent
metastasis by inhibiting tumour cell invasion,2,4e6 tumour-
associated inflammation, and vasculature remodelling to
limit tumour cell dissemination.5,7
The perioperative period is a critical stage of a patient’s
cancer journey. While surgery is essential for the curative
treatment of many solid tumours, the biological perturbation
associated with the surgical stress response has been
increasingly implicated in cancer recurrence.8e10 Studies in
mouse models of cancer show that surgical stress elevates
tumour cell retention in metastatic target organs, and these
effects may be blocked by beta-blockers.11
To date, a variable association between beta-blocker use
and cancer outcomes is reported in clinical cohort studies. A
systematic review and meta-analysis was undertaken to
investigate the clinical relationship between beta-blocker use
and cancer recurrence (CR), disease-free survival (DFS), and
overall survival (OS). The analysis investigated the effect of co-
incidental beta-blocker (selective and non-selective) use at
cancer diagnosis (referenced as epidemiological studies), and
specifically in patients undergoing surgery (referenced as
perioperative studies) on long-term cancer outcomes. Studies
were also analysed for immortal time bias (ITB), a bias created
when a period exists during which the outcome of interest for
one of the cohorts cannot possibly occur because of the study
design.12 Also known as survivor (ship) bias,12,13 ITB has been
noted to over-represent patients with high mortality in the no
treatment group and patients with low mortality in the treat-
ment group.14
Methods
Protocol and registration
This systematic review was conducted in accordance to the
Cochrane methodology and the results are reported according
to the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) statement. The review protocol
was registered with PROSPERO (Registration Number:
CRD42015030102).
Systematic literature search
The following electronic databases were searched for periods
up to and including September 2017: Medline (Ovid,
1946epresent), EMBASE (Ovid, 1947epresent), Web of Science
(ThomsoneReuters, 1900epresent), and all components of the
Cochrane Library (Wiley, all years). The systematic search
excluded animal-only and non-English publications and was
limited to studies in adult patients. To maximise sensitivity,
each database was searched using two different search stra-
tegies and the results merged. The first strategy focused on
beta-blocker use and cancer recurrence or survival, and the
second strategy targeted the surgical stress response and
cancer recurrence or survival. The search strategies contained
a combination of controlled vocabulary (e.g. MeSH, EMTREE)
and keyword terms and phrases searched in titles, abstracts,
and keyword fields as appropriate. Both drug class and generic
names of commonly used adrenergic agents (beta-blockers
and beta-agonists) and catecholamines (in particular
epinephrine, norepinephrine, noradrenaline, and adrenaline),
and sympathetic stress response terms were included in the
search strategies. An EndNote library was used to manage
retrieved records and for de-duplication. The detailed search
strings used in the Medline database are listed in
Supplementary Digital Content 1.
Study selection and eligibility criteria
Three reviewers (A.Y., J.D., and R.S.) independently screened
all retrieved records. Disagreements were resolved through
discussion and consensus. When no consensus was reached,
an additional investigator acted as an adjudicator (B.R.).
Comparative studies (i.e. cohorts and caseecontrol studies)
that examined the effect of any of the beta-blockers (selective
and non-selective) on cancer outcomes (e.g. recurrence,
relapse, metastasis, disease progression, survival, mortality)
were included. Studies evaluating beta-blockers in non-solid
organ tumours or evaluating the effect of beta-blockers on
the epidemiological risk of developing cancer were excluded.
Data collection process and data items
Data from each study were independently extracted by two
authors (A.Y. and J.D.), and cross-checked by a different author
(R.S.). A standardised extraction form was used to collect in-
formation about the characteristics of the studies and their
participants, types of interventions, reported outcomes, and
sources of funding. Information documented included author
name, year of publication, country of publication, study
design, type of cancer, sample size, beta-blocker use (subtype
and timing in relation to cancer diagnosis), other

antihypertensive use, exposure during cancer treatment, and
the setting of data collection (e.g. multicentre study, large
teaching hospital).
Statistical analysis
Analyses were conducted using RevMan 5.2.3 and STATA
Version 14 for meta-regression (StataCorp LP, College Station,
TX, USA). We transformed reported hazard ratio (HR) estimates
into log hazard ratesda recommended single summary sta-
tistic for quantifying the treatment effect in studies reporting
survival data. The extracted 95% confidence intervals (95% CIs)
were transformed to standard errors. The generic inverse-
variance method with random-effects model was used for
pooled estimates. When more than one data set was provided,
the post cancer diagnosis beta-blocker data and adjusted ratios
after cancer diagnosis were used for the primary analyses. If
data were not provided in HR or there were missing or incom-
plete data, an attempt was made to contact the original study
authors. Comparisons within the meta-analysis explored the
use of ‘any’ vs ‘no’ b-blocker use in all the studies. Sub-analyses
investigated ‘non-selective’ vs ‘no’ beta-blocker use, the peri-
operative use of beta-blockers, and cancer type.
Assessment of bias in individual studies
Two investigators (A.Y. and J.D.) independently assessed
methodological quality using the NewcastleeOttawa Scale
(NOS). The NOS is a validated tool for the assessment of bias in
non-randomised studies.15 The tool uses a scoring system to
judge the selection process of the study groups (up to 4 points),
the comparability of the groups (up to 2 points), and the
ascertainment of exposure and outcome in the studies (up to 3
points). A maximum score of 9 points can be obtained, with
studies with scores 7 points generally regarded as having
higher quality and a lower risk of bias.16 Discrepancies were
resolved by consensus and when this was not reached a third
person (R.S.) acted as an adjudicator.
Risk of bias across studies and additional analyses
A funnel plot and a regression asymmetry test17 was per-
formed to assess publication bias and small-study effects in
the meta-analyses for overall survival. When the estimates
differed substantially among the pooled studies (c2 test,
P>0.10), potential predictors of heterogeneity were explored
through sub-group analysis, sensitivity analysis by type of
estimate (adjusted or unadjusted), or meta-regression to
explore the effect of study quality on the results.18 We also
evaluated for the impact of ITB.12
Results
Study selection and characteristics
Sixty-four studies matched the eligibility criteria (Fig. 1) and
data for quantitative synthesis were available in 27 studies
(Table 1).19e45 The majority of studies used b1AR selective
beta-blockers. All the studies were cohort studies and two
studies were prospective.38,44 Two studies evaluated the
effect of beta-blockers in more than one cancer type.29,37
Nine studies evaluated non-selective beta-blocker use at
cancer diagnosis24,30,31,37e39,41,42,44 and 10 studies evaluated
perioperative beta-blocker use in patients undergoing
surgery.19,21,22,24,26,32,33,36,41,45
Beta-blockers, cancer recurrence, and survival - 3
Beta-blocker use in any setting (epidemiological or
perioperative)
Cancer recurrence
Seven studies (six retrospective21,22,28,30,32,34 and one pro-
spective38) evaluated CR in patients receiving ‘any’ vs ‘no’
beta-blocker (Fig. 2). None of the results were statistically
significant. Two studies30,38 evaluated CR in patients receiving
‘non-selective’ beta-blockers but no significant effect was
observed on CR.
A subgroup analysis was undertaken to determine if the
study design (retrospective vs prospective) contributed to the
heterogeneity of the final result for ‘any’ vs ‘no’ beta-blocker
use and CR. In this subgroup analysis, it was noted that
there was statistical difference between the one prospective
study38 and the retrospective studies,21,22,28,30,32,34 (P<0.01),
indicating that the temporality of the methodology in the re-
ported studies was affecting the results. The prospective study
by Sorensen and colleagues38 reported that patients receiving
beta-blockers had a higher risk of breast CR when compared
with non-users (HR 1.30, 95% CI 1.10e1.50; P0.01).
Disease-free survival
Ten studies,19,24,25,31,33,35,36,40,41,45 all retrospective in nature,
investigated the association between ‘any’ vs ‘no’ beta-blocker
use and DFS (Fig. 3). The pooled HR for all cancer types was not
statistically significant (HR 0.78, 95% CI 0.54e1.11; P¼0.17).
Exploring cancer types, there was an associated improve-
ment in DFS with beta-blocker use in patients with melanoma
(one study25: HR 0.03, 95% CI 0.01e0.17; P<0.01) and a reduction
in DFS reported in patients with endometrial cancer (one
study35: HR 1.40, 95% CI 1.10e1.80; P<0.01).
Four studies (three retrospective24,31,41 and one prospec-
tive44) evaluated the effect of ‘non-selective’ beta-blocker use
on DFS. The pooled HR for all cancer types was not statistically
significant. Within cancer types, an associated improvement
in DFS was noted with non-selective beta-blocker use in
melanoma (one study44: HR 0.18, 95% CI 0.04e0.89; P¼0.03) and
ovarian cancer (one study41: HR 0.08, 95% CI 0.03e0.22; P<0.01).
In a subgroup analysis looking at study design, no statistically
significant differences were observed between the one pro-
spective study44 and the retrospective studies (P¼0.34).24,31,41
Overall survival
Eighteen studies,19,20,23e27,29,31,32,35,37,39e43,45 all retrospective,
investigated the association between ‘any’ vs ‘no’ beta-blocker
use and OS (Fig. 4). The pooled HR found no association with
b-blocker use and overall survival (HR 1.00, 95% CI 0.90e1.12;
P¼0.99). Exploring cancer types, beta-blocker use was associ-
ated with improved OS in patients with melanoma (one study25:
HR 0.04, 95% CI 0.00e0.38; P<0.01) but decreased OS in endo-
metrial (one study35: HR 1.50, 95% CI 1.12e2.00; P<0.01), head and
neck (one study31: HR 1.64, 95% CI 1.23e2.20; P<0.01), and pros-
tate cancer (two studies29,37: HR 1.31, 95% CI 1.01e1.68; P¼0.04).
Seven studies (six retrospective24,31,37,39,41,42 and one pro-
spective44) examined the effect of ‘non-selective’ beta-blocker
use on OS. The pooled HR for all cancer types was not statis-
tically significant. Examining cancer types, disparity was
noted in single studies, with improved OS observed with non-
selective beta-blocker use in ovarian cancer (one study41: HR
0.08, 95% CI 0.03e0.22; P<0.01) and reduced OS reported in lung
cancer (one study42: HR 1.26, 95% CI 1.06e1.49; P¼0.01).
 4 - Yap et al.
Fig 1. Prisma flow diagram of the systematic literature search.
The only prospective study, by De Giorgi and colleagues,44
found no association with OS with non-selective beta-
blocker use in patients with melanoma (HR 0.64, 95% CI
0.10e3.96; P¼0.63). In a subgroup analysis assessing study
design, no statistically significant difference was found be-
tween the one prospective study44 and the retrospective
studies.24,31,37,39,41,42
Beta-blocker use in the perioperative setting
Supplementary Table S1 displays the association between
beta-blocker use around the time of surgery and
cancer outcomes for the 10 retrospective perioperative
studies.19,21,22,24,26,32,33,36,41,45 The only statistically significant
association was found in the study by Watkins and col-
leagues41 who reported that use of non-selective beta-blockers
in patients with ovarian cancer was associated with improved
DFS (HR 0.08, 95% CI 0.03e0.22; P<0.01) and OS (HR 0.08, 95% CI
0.03e0.22; P<0.01).
Risk of bias across studies
The majority (93%) of the studies had a total NOS score 7.
Removing studies19,20,22,24,28,32,41,43,45 with a risk of ITB from
the analysis resulted in an associated reduction in CR in
patients with breast cancer or an associated improvement
in OS in patients with ovarian cancer using any beta-blocker
in the perioperative period (Supplementary Table S2). Two
studies25,26 were excluded from the ITB analysis as there
was not enough information available to determine if there
was a risk of ITB. Egger’s test showed no evidence for
publication bias even when outliers were removed. When
studies with extrapolated data from ‘risk of metastasis’ or
‘relapse-free survival’ were removed from the analysis of
cancer recurrence, no differences were observed in any of
the outcomes.
Discussion
We conducted a meta-analysis investigating the effect of
beta-blockers on long-term cancer outcomes in both the
epidemiological (non-perioperative) and perioperative set-
tings. Based on the mostly retrospective studies identified,
the use of beta-blockers in patients with cancer appears to
have no consistent association with cancer recurrence or
survival in either the epidemiological or perioperative setting.
Beta-blocker use may be associated with better outcomes in
specific types of cancer (e.g. melanoma and ovarian cancer),
while an opposite effect was observed in patients with
endometrial, prostate, head and neck, or lung cancer. The
lack of causal relationship and specificity46 between beta-
blocker therapy and long-term cancer outcomes in the
epidemiological studies examined (Supplementary Table S3)
may reflect the paucity of data but may also reflect the un-
derlying heterogeneity in the response of cancer subtypes to
beta-blocker modulation.
Differential bAR subtype expression (b1, b2, or b3)47 is found
on cancer cells and immune cells, and activation of these re-
ceptors in different cancer types has diverse effects on the
tumour microenvironment (tumour proliferation, migration
and invasion).48 Importantly, in vivo studies that explore the
effects of bAR signalling suggest a key role for the b2AR in
modulating tumour outcomes, and typically investigated b-
blockade using propranolol, a non-selective beta-block-
er.3e5,7,11,49 In contrast, the majority of clinical studies
included in this meta-analysis investigated effects from the
b1AR-selective blocker, metoprolol. Where the use of non-
selective beta-blockers were analysed, an improvement in
DFS and OS was noted for patients with ovarian cancer,
although the results were from a single study by Watkins and
colleagues.41 This study does, however, support the in vitro
evidence that ovarian cancer is affected by activation of the b2
adrenergic pathway, and thus susceptible to blockade by
propranolol.49
The potential benefit of non-selective beta-blockers in the
perioperative setting on CR and OS is supported by recent
randomised placebo-controlled trials by Zhou and col-
leagues50 and Shaashua and colleagues.51 In these periopera-
tive studies of patients with breast cancer, propranolol
treatment preserved the anticancer immunological profiles of
peripheral blood mononuclear cells, and reduced epithelial-to-
mesenchymal transition and activity of prometastatic and
proinflammatory transcription factors in excised tumours
when compared with placebo. In addition, Shaashua and col-
leagues51 suggested a synergistic beneficial effect may be
revealed with the concurrent administration of anti-
inflammatory and beta-blocker interventions. Several pro-
spective clinical trials are currently assessing propranolol use
in patients with breast (NCT00502684, NCT01847001,
NCT02596867), ovarian (NCT01308944, NCT01504126), mela-
noma (NCT01988831), and colorectal cancer (NCT00888797)
and will shed additional light on oncological outcomes after
surgery. In contrast to the POISE study52 which investigated
the effects of perioperative metoprolol, the above clinical trials
Table 1 Characteristics of the 27 studies included in the meta-analysis separated by cancer type. * ¼ cancer recurrence results calculated from the original published data; y ¼ disease free
survival results calculated from the original published data; z ¼ only abstracts available for analysis

Study (1st Sample NOS Study design Beta-blocker subtype Cancer outcomes Assessed non- Assessed Possibility of
author, Ref) size score used in the study assessed selective perioperative immortal
beta-blocker use beta-blocker use time bias

Breast
Botteri21 800 8 Retrospective Atenolol Cancer recurrence* No Yes No
Betaxolol
Bisoprolol
Carvedilol
Metoprolol
Nebivolol
Sotalol
Boudreau22 4216 8 Retrospective Atenolol Cancer recurrence No Yes Yes
Metoprolol
Other (not stated)
Ganz28 1779 8 Retrospective Atenolol Cancer recurrence No No Yes
Metoprolol
Propranolol
Other (not stated)
Holmes29 4019 6 Retrospective Not stated Overall survival No No No
Melhem- 1413 8 Retrospective Atenolol Cancer recurrence* No Yes Yes
Bertrandt32 Metoprolol Overall survival
Other (not stated)
Powe34 466 8 Retrospective Atenolol Cancer recurrence* No No No
Bisoprolol
Propranolol
Timolol

Beta-blockers, cancer recurrence, and survival

Sakellakis36 610 9 Retrospective Not stated Disease-free survival No Yes No
Shah37 984 8 Retrospective Atenolol Overall survival Yes No No
Propranolol
Other (not stated)
Sorensen38 18 733 9 Prospective Acebutolol Cancer recurrence Yes No No
Alprenolol
Atenolol
Betaxolol
Bisoprolol
Carvedilol
Labetalol
Metoprolol
Nebivolol
Oxprenolol
Pindolol
Propranolol
Sotalol
Timolol
Colorectal
Engineer27 262 8 Retrospective Not stated Overall survival No No No
Holmes29 3967 6 Retrospective Not stated Overall survival No No No

-
Jansen30 1820 8 Retrospective Cancer recurrence Yes No No

5
Continued
Table 1 Continued

6
Study (1st Sample NOS Study design Beta-blocker subtype Cancer outcomes Assessed non- Assessed Possibility of

-
author, Ref) size score used in the study assessed selective perioperative immortal

Yap et al.
beta-blocker use beta-blocker use time bias

Acebutolol
Atenolol
Betaxolol
Bisoprolol
Carteolol
Carvedilol
Celiprolol
Esmolol
Metoprolol
Nadolol
Nebivolol
Penbutolol
Pindolol
Propranolol
Sotalol
Timolol
Shah37 619 8 Retrospective Atenolol Overall survival Yes No No
Propranolol
Other (not stated)
Endometrial
Roque35z 1964 7 Retrospective Not stated Overall survival Not stated No No
Head and neck
Kim31 1274 7 Retrospective Atenolol Disease-free survival, Yes No No
Bisoprolol overall survival
Carvedilol
Metoprolol
Propranolol
Sotalol
Timolol
Lung excluding non-small cell lung cancer
Holmes29 4241 7 Retrospective Not stated Overall survival No No No
Shah37 436 9 Retrospective Atenolol Overall survival Yes No No
Propranolol
Other (not stated)
Weberpals42 3340 8 Retrospective Atenolol Overall survival Yes No No
Bisoprolol
Metoprolol
Sotalol
Melanoma
De Giorgi25 741 8 Retrospective Atenolol Disease-free survival, No No Unable to
Betaxolol overall survival assess
Bisoprolol
Carvedilol
Labetalol
Metoprolol
Nadolol
Nebivolol

Continued
Table 1 Continued

Study (1st Sample NOS Study design Beta-blocker subtype Cancer outcomes Assessed non- Assessed Possibility of
author, Ref) size score used in the study assessed selective perioperative immortal
beta-blocker use beta-blocker use time bias

Propranolol
Sotalol
Timolol
De Giorgi44 53 7 Prospective Propranolol Disease-free survival, Yes No No
overall survival
Non-small cell lung cancer
Aydiner20 107 8 Retrospective Atenolol Overall survival No No Yes
Carvedilol
Metoprolol
Nebivolol
Cata24 435 9 Retrospective Atenolol Disease-free survivaly Yes Yes Yes
Bisoprolol Overall survival
Carvedilol
Labetalol
Metoprolol
Nadolol
Propranolol
Wang40 722 9 Retrospective Atenolol Disease-free survival, No No No
Bisoprolol overall survival
Carvedilol
Nadolol
Labetalol
Metoprolol
Propranolol
Sotalol

Beta-blockers, cancer recurrence, and survival

Yang43 606 8 Retrospective Not stated Overall survival No No Yes
Oesophagus
Shah37 159 8 Retrospective Atenolol Overall survival Yes No No
Propranolol
Other (not stated)
Ovarian
Al-Niaimi19 185 8 Retrospective Metoprolol Disease-free survivaly No Yes Yes
overall survival
Brown23z 3097 7 Retrospective Not stated Overall survival No No No
Diaz26 284 6 Retrospective Atenolol Overall survival No Yes Unable to
Carvedilol assess
Labetalol
Metoprolol
Propranolol
Heitz45 561 7 Retrospective Atenolol Disease-free survivaly No Yes Yes
Bisoprolol overall survival
Metoprolol
Nebivolol
Shah37 148 8 Retrospective Atenolol Overall survival Yes No No
Propranolol
Other (not stated)

-
7
Continued
Table 1 Continued

8
Study (1st Sample NOS Study design Beta-blocker subtype Cancer outcomes Assessed non- Assessed Possibility of

-
author, Ref) size score used in the study assessed selective perioperative immortal

Yap et al.
beta-blocker use beta-blocker use time bias

Watkins41 1425 9 Retrospective Not stated Disease-free survivaly Yes Yes Yes
overall survival
Pancreas
Shah37 140 9 Retrospective Atenolol Overall survival Yes No No
Propranolol
Other (not stated)
Udumyan39 2394 9 Retrospective Atenolol Overall survival Yes No No
Bisoprolol
Metoprolol
Propranolol
Prostate
Holmes29 3355 6 Retrospective Not stated Overall survival No No No
Shah37 759 8 Retrospective Atenolol Overall survival Yes No No
Propranolol
Other (not stated)
Renal
Parker33 913 9 Retrospective Atenolol, Disease-free survivaly No Yes No
Carvedilol
Labetalol
Metoprolol
Nadolol
Nebivolol
Propranolol
Shah37 124 8 Retrospective Atenolol Overall survival Yes No No
Propranolol
Other (not stated)
Stomach
Shah37 93 8 Retrospective Atenolol Overall survival Yes No No
Propranolol
Other (not stated)

Fig 2. Cancer recurrence: Comparison of ‘any’ beta-blocker vs ‘no’ beta-blocker use.
use propranolol and this beta-blocker may have different
physiological effects because of its broad receptor activity.
Weberpals and colleagues53,54 conducted two meta-
analyses on beta-blocker use and cancer prognosis and spe-
cifically evaluated the impact of ITB. The authors concluded
that the beneficial effect of beta-blockers on cancer survival in
previous studies may have been a result of ITB and that the
magnitude of ITB depends on the duration of excluded
immortal time and the prognosis of each cancer.53,54 In our
meta-analysis, we considered ITB and excluded potentially
affected studies in a subgroup analysis.19,20,22,24,28,32,41,43,45
Correcting for ITB had no substantive effect on our results:
the only changes noted were an associated reduction in breast
CR, and improved OS in ovarian cancer patients taking any
type of beta-blocker perioperatively. Furthermore, after
correction for ITB, only a single perioperative study (rather
than pooled data) remained for the perioperative analysis,
which is a significant limitation.
Another major limitation of this meta-analysis is the sig-
nificant heterogeneity of conditions analysed in the studies,
Beta-blockers, cancer recurrence, and survival - 9
including the large number of cancer types, the variety of beta-
blockers used, the indications for beta-blocker use (e.g. con-
founding by indication in the epidemiological setting), and the
unknown differences in bAR expression on each cancer type
and on immune cells. Furthermore, inadequate data on the
various cancer treatment regimens (such as chemotherapy,
radiotherapy and surgery) and staging of the disease may ac-
count for the conflicting results across cancer types, limiting
the ability to detect an association between beta-blocker use
and long-term cancer outcomes.
In summary, this meta-analysis of clinical studies has
found that beta-blocker use has no overall effect on cancer
recurrence, disease-free survival and overall survival. Within
cancer subgroups, the beneficial effect of beta-blockers re-
mains variable, tumour-specific, and of low-level evidence at
present. Given the persuasive in vivo findings and recent
prospective clinical evaluation of beta-blockers,44,51 further
clinical evaluation within specific cancer subtypes using
randomised controlled trials will determine if beta-blockers
have a therapeutic benefit in cancer recurrence and survival.
 10 - Yap et al.

Fig 3. Disease-free survival: comparison of ‘any’ beta-blocker vs ‘no’ beta-blocker use.

 Beta-blockers, cancer recurrence, and survival - 11

Fig 4. Overall survival: Comparison of ‘any’ beta-blocker vs ‘no’ beta-blocker use.

 12 - Yap et al.
Authors’ contributions
Study conception and design: A.Y., R.S.
Acquisition of data: A.Y., R.S.
Analysis and interpretation of data: A.Y., R.S.
Drafting and revision of the manuscript: A.Y., M. L.-O., R.S.
Final approval of the version to be published: all authors.
Data analysis: M. L.-O.
Study design: J.D., B.R.
Data collection: J.D., G.P.,
Revision of the manuscript: J.D., G.P., J.H., V.G., E.S., B.R.
Data interpretation: J.H., V.G., E.S., B.R.
Acknowledgements
The authors thank Dr Mike Hernandez (The University of
Texas M.D. Anderson Cancer Center, Houston, TX, USA) for
support with statistical analysis.
Declaration of interest
The authors declare that they have no conflicts of interest.
Funding
National Health and Medical Research Council of Australia
(1147498), the Australian and New Zealand College of Anaes-
thetists (17/003), and the David and Lorelle Skewes Founda-
tion. Career award from the Rheumatology Research
Foundation, USA to M. L.-O.
Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.bja.2018.03.024.
References
1. Frishman WH. beta-Adrenergic blockers: a 50-year his-
torical perspective. Am J Ther 2008; 15: 565e76
2. Creed SJ, Le CP, Hassan M, et al. beta2-adrenoceptor
signaling regulates invadopodia formation to enhance
tumor cell invasion. Breast Cancer Res 2015; 17: 145
3. Benish M, Bartal I, Goldfarb Y, et al. Perioperative use of
beta-blockers and COX-2 inhibitors may improve immune
competence and reduce the risk of tumor metastasis. Ann
Surg Oncol 2008; 15: 2042e52
4. Chang A, Le CP, Walker AK, et al. beta2-Adrenoceptors on
tumor cells play a critical role in stress-enhanced metas-
tasis in a mouse model of breast cancer. Brain Behav
Immun 2016; 57: 106e15
5. Sloan EK, Priceman SJ, Cox BF, et al. The sympathetic
nervous system induces a metastatic switch in primary
breast cancer. Cancer Res 2010; 70: 7042e52
6. Pon CK, Lane JR, Sloan EK, Halls ML. The beta2-
adrenoceptor activates a positive cAMP-calcium feedfor-
ward loop to drive breast cancer cell invasion. FASEB J
2016; 30: 1144e54
7. Le CP, Nowell CJ, Kim-Fuchs C, et al. Chronic stress in
mice remodels lymph vasculature to promote tumour cell
dissemination. Nat Commun 2016; 7: 10634
8. Dillekas H, Demicheli R, Ardoino I, Jensen SA, Biganzoli E,
Straume O. The recurrence pattern following delayed
breast reconstruction after mastectomy for breast cancer
suggests a systemic effect of surgery on occult dormant
micrometastases. Breast Cancer Res Treat 2016; 158: 169e78
9. Horowitz M, Neeman E, Sharon E, Ben-Eliyahu S. Exploit-
ing the critical perioperative period to improve long-term
cancer outcomes. Nat Rev Clin Oncol 2015; 12: 213e26
10. Hiller JG, Perry NJ, Poulogiannis G, Riedel B, Sloan EK.
Perioperative events influence cancer recurrence risk af-
ter surgery. Nat Rev Clin Oncol 2018; 15: 205e18
11. Melamed R, Rosenne E, Shakhar K, Schwartz Y,
Abudarham N, Ben-Eliyahu S. Marginating pulmonary-NK
activity and resistance to experimental tumor metastasis:
suppression by surgery and the prophylactic use of a beta-
adrenergic antagonist and a prostaglandin synthesis in-
hibitor. Brain Behav Immun 2005; 19: 114e26
12. Suissa S. Immortal time bias in pharmaco-epidemiology.
Am J Epidemiol 2008; 167: 492e9
13. Ho AM, Dion PW, Ng CS, Karmakar MK. Understanding
immortal time bias in observational cohort studies.
Anaesthesia 2013; 68: 126e30
14. Schmidt SA, Schmidt M. Beta-blockers and improved
survival from ovarian cancer: New miracle treatment or
another case of immortal person-time bias? Cancer 2016;
122: 324e5
15. Wells GASB, O’Connell D, Peterson J, Welch V, Losos M,
Tugwell P. The Newcastle-Ottawa Scale (NOS) for assess-
ing the quality of nonrandomised studies in meta-analyses.
2008
16. Stang A. Critical evaluation of the Newcastle-Ottawa scale
for the assessment of the quality of nonrandomized
studies in meta-analyses. Eur J Epidemiol 2010; 25: 603e5
17. Sterne JA, Egger M. Funnel plots for detecting bias in
meta-analysis: guidelines on choice of axis. J Clin Epidemiol
2001; 54: 1046e55
18. Thompson SG, Higgins JP. How should meta-regression
analyses be undertaken and interpreted? Stat Med 2002;
21: 1559e73
19. Al-Niaimi A, Dickson EL, Albertin C, et al. The impact of
perioperative beta blocker use on patient outcomes after
primary cytoreductive surgery in high-grade epithelial
ovarian carcinoma. Gynecol Oncol 2016; 143: 521e5
20. Aydiner A, Ciftci R, Karabulut S, Kilic L. Does beta-blocker
therapy improve the survival of patients with metastatic
non-small cell lung cancer? Asian Pac J Cancer Prev 2013;
14: 6109e14
21. Botteri E, Munzone E, Rotmensz N, et al. Therapeutic ef-
fect of beta-blockers in triple-negative breast cancer
postmenopausal women. Breast Cancer Res Treat 2013; 140:
567e75
22. Boudreau DM, Yu O, Chubak J, et al. Comparative safety of
cardiovascular medication use and breast cancer out-
comes among women with early stage breast cancer.
Breast Cancer Res Treat 2014; 144: 405e16
23. Brown C, Barron T, Bennett K, Sharp L. Associations be-
tween pre- and post-diagnostic use of beta-blockers and
ovarian cancer survival. Eur J Cancer Care 2015; 24: 21
24. Cata JP, Villarreal J, Keerty D, et al. Perioperative beta-
blocker use and survival in lung cancer patients. J Clin
Anesth 2014; 26: 106e17
25. De Giorgi V, Gandini S, Grazzini M, Benemei S,
Marchionni N, Geppetti P. Effect of beta-blockers and
other antihypertensive drugs on the risk of melanoma
recurrence and death. Mayo Clinic Proc 2013; 88:
1196e203

26. Diaz ES, Karlan BY, Li AJ. Impact of beta blockers on
epithelial ovarian cancer survival. Gynecol Oncol 2012; 127:
375e8
27. Engineer DR, Burney BO, Hayes TG, Garcia JM. Exposure to
ACEI/ARB and beta-blockers is associated with improved
survival and decreased tumor progression and hospitali-
zations in patients with advanced colon cancer. Transl
Oncol 2013; 6: 539e45
28. Ganz PA, Habel LA, Weltzien EK, Caan BJ, Cole SW.
Examining the influence of beta blockers and ACE in-
hibitors on the risk for breast cancer recurrence: results
from the LACE cohort. Breast Cancer Res Treat 2011; 129:
549e56
29. Holmes S, Griffith EJ, Musto G, Minuk GY. Antihyperten-
sive medications and survival in patients with cancer: a
population-based retrospective cohort study. Cancer Epi-
demiol 2013; 37: 881e5
30. Jansen L, Hoffmeister M, Arndt V, Chang-Claude J,
Brenner H. Stage-specific associations between beta
blocker use and prognosis after colorectal cancer. Cancer
2014; 120: 1178e86
31. Kim SA, Moon H, Roh JL, et al. Postdiagnostic use of beta-
blockers and other antihypertensive drugs and the risk of
recurrence and mortality in head and neck cancer pa-
tients: an observational study of 10,414 person-years of
follow-up. Clin Transl Oncol 2017; 19: 1e8
32. Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, et al.
Beta-blocker use is associated with improved relapse-free
survival in patients with triple-negative breast cancer.
J Clin Oncol 2011; 29: 2645e52
33. Parker WP, Lohse CM, Zaid HB, et al. Evaluation of beta-
blockers and survival among hypertensive patients with
renal cell carcinoma. Urol Oncol 2017; 35. 36.e1e6
34. Powe DG, Voss MJ, Zanker KS, et al. Beta-blocker drug
therapy reduces secondary cancer formation in breast
cancer and improves cancer specific survival. Oncotarget
2010; 1: 628e38
35. Roque DR, Pierce S, Doll KM, et al. Endometrial cancer
outcomes in hypertensive women treated with beta-
blocker. J Clin Oncol 2014; 32: 15
36. Sakellakis M, Kostaki A, Starakis I, Koutras A. Beta-blocker
use and risk of recurrence in patients with early breast
cancer. Chemotherapy 2014; 60: 288e9
37. Shah SM, Carey IM, Owen CG, Harris T, Dewilde S,
Cook DG. Does beta-adrenoceptor blocker therapy
improve cancer survival? Findings from a population-
based retrospective cohort study. Br J Clin Pharmacol
2011; 72: 157e61
38. Sorensen GV, Ganz PA, Cole SW, et al. Use of beta-
blockers, angiotensin-converting enzyme inhibitors,
angiotensin II receptor blockers, and risk of breast cancer
recurrence: a Danish nationwide prospective cohort
study. J Clin Oncol 2013; 31: 2265e72
39. Udumyan R, Montgomery S, Fang F, et al. Beta-blocker
drug use and survival among patients with pancreatic
adenocarcinoma. Cancer Res 2017; 77: 3700e7
Beta-blockers, cancer recurrence, and survival - 13
40. Wang HM, Liao ZX, Komaki R, et al. Improved survival
outcomes with the incidental use of beta-blockers among
patients with non-small-cell lung cancer treated with
definitive radiation therapy. Ann Oncol 2013; 24: 1312e9
41. Watkins JL, Thaker PH, Nick AM, et al. Clinical impact of
selective and nonselective beta-blockers on survival in
patients with ovarian cancer. Cancer 2015; 121: 3444e51
42. Weberpals J, Jansen L, Haefeli WE, et al. Pre- and post-
diagnostic beta-blocker use and lung cancer survival: a
population-based cohort study. Sci Rep 2017; 7: 2911
43. Yang P, Deng W, Han Y, et al. Analysis of the correlation
among hypertension, the intake of beta-blockers, and
overall survival outcome in patients undergoing chemo-
radiotherapy with inoperable stage III non-small cell lung
cancer. Am J Cancer Res 2017; 7: 946e54
44. De Giorgi V, Grazzini M, Benemei S, et al. Propranolol for
off-label treatment of patients with melanoma: results
from a cohort study. JAMA Oncol 2018; 4: e172908
45. Heitz F, Hengsbach A, Harter P, et al. Intake of selective
beta blockers has no impact on survival in patients with
epithelial ovarian cancer. Gynecol Oncol 2017; 144: 181e6
46. Hill AB. The environment and disease: association or
causation? Proc R Soc Med 1965; 58: 295e300
47. Rains SL, Amaya CN, Bryan BA. Beta-adrenergic receptors
are expressed across diverse cancers. Oncoscience 2017; 4:
95e105
48. Tang J, Li Z, Lu L, Cho CH. beta-Adrenergic system, a
backstage manipulator regulating tumour progression
and drug target in cancer therapy. Semin Cancer Biol 2013;
23: 533e42
49. Thaker PH, Han LY, Kamat AA, et al. Chronic stress pro-
motes tumor growth and angiogenesis in a mouse model
of ovarian carcinoma. Nat Med 2006; 12: 939e44
50. Zhou L, Li Y, Li X, et al. Propranolol attenuates surgical
stress-induced elevation of the regulatory T cell response
in patients undergoing radical mastectomy. J Immunol
2016; 196: 3460e9
51. Shaashua L, Shabat-Simon M, Haldar R, et al. Periopera-
tive COX-2 and beta-adrenergic blockade improves met-
astatic biomarkers in breast cancer patients in a phase-II
randomized trial. Clin Cancer Res 2017; 23: 4651e61
52. Group PS, Devereaux PJ, Yang H, et al. Effects of extended-
release metoprolol succinate in patients undergoing non-
cardiac surgery (POISE trial): a randomised controlled
trial. Lancet 2008; 371: 1839e47
53. Weberpals J, Jansen L, Carr PR, Hoffmeister M, Brenner H.
Beta blockers and cancer prognosis - the role of immortal
time bias: a systematic review and meta-analysis. Cancer
Treat Rev 2016; 47: 1e11
54. Weberpals J, Jansen L, van Herk-Sukel MPP, et al.
Immortal time bias in pharmacoepidemiological studies
on cancer patient survival: empirical illustration for beta-
blocker use in four cancers with different prognosis. Eur J
Epidemiol 2017; 32: 1019e31
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