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. 2021 Feb 16;16(2):e0245773. doi: 10.1371/journal.pone.0245773

Beta-blocker and survival in patients with lung cancer: A meta-analysis

Zhen Lei 1, Weiyi Yang 1, Ying Zuo 2,*
Editor: Jianxin Xue3
PMCID: PMC7886135  PMID: 33592015

Abstract

Background

Beta-blocker (BB) is suggested to have anticancer efficacy. However, the potential influence of BB use on overall survival (OS) in patients with lung cancer remains undetermined. We aimed to evaluate the above relationship in an updated meta-analysis.

Methods

Observational studies comparing OS between users and non-users of BB with lung cancer were identified by search of PubMed, Embase, and Cochrane’s Library. A random-effect model was used to pool the results.

Results

Ten retrospective cohort studies with 30870 patients were included. Overall, BB use was not associated with significantly improved OS in lung cancer (hazard ratio [HR] = 1.02, 95% confidence interval [CI]: 0.98 to 1.06, p = 0.33) with moderate heterogeneity (I2 = 29%). Stratified analyses showed similar results in patients with non-small cell lung cancer and small cell lung cancer, in studies with BB use before and after the diagnosis of lung cancer, and in studies with or without adjustment of smoking. Use of BB was associated with improved OS in patients with stage III lung cancer (HR = 0.91, 95% CI: 0.85 to 0.98, p = 0.02) and in patients that did not receive surgery resection (HR = 0.78, 95% CI: 0.64 to 0.96, p = 0.02), while use of non-selective BB was associated with worse OS (HR = 1.14, 95% CI: 1.01 to 1.28, p = 0.03).

Conclusions

This meta-analysis of retrospective cohort studies does not support a significant association between BB use and improved OS in lung cancer.

Introduction

Lung cancer is one of the most common cancers worldwide [1, 2]. Moreover, lung cancer is also the leading cause of cancer-specific mortality for the global population, which results in more than 1.7 million deaths annually [1, 2]. Lung cancer can be broadly divided into two categories, including small-cell lung cancer (SCLC) which accounts for about 15% of the cases, and non-small cell lung cancer (NSCLC) which accounts for about 85% of the cases [3]. Although current comprehensive treatment strategies, including surgery resection, chemotherapy, radiotherapy, immune therapy, and targeted therapy have shown promising efficacy in patients of lung cancer, the prognosis of these patients remains poor [4, 5]. Therefore, identification of additional treatments for lung cancer remains of great clinical significance [6, 7]. Preclinical studies demonstrated that chronic stress accelerates the process of carcinogenesis via increasing the serum level of catecholamine and subsequent activation of adrenergic receptors in target tissues, including cancer cells [8]. Indeed, the activation of beta adrenergic receptor axis in cancer has been related with stimulated angiogenesis, enhanced expression of genes in metastasis and inflammation, upregulated cancer cell proliferation, and modulated tumor immune microenvironment, which are all key pathophysiological processes in tumorigenesis, angiogenesis, and tumor metastasis [8–10]. Accordingly, use of beta-blocker (BB) has been hypothesized to confer anticancer efficacy by targeted inhibition of beta adrenergic receptor axis in tumor development and progression [11]. Previous studies have confirmed that use of BB is related with reduced incidence of liver cancer [12] and improved survival in prostate cancer [13]. However, studies evaluating the association between BB use and survival of lung cancer showed inconsistent results [14–23]. An early study showed that the incidental use of BB among patients with NSCLC treated with definitive radiation therapy was associated with improved survival [17]. However, other studies failed to detect a potential benefit of BB use on survival in patients with lung cancer [14–16, 18–23]. Moreover, although a few meta-analyses have been published to evaluate the influence of BB use on survival of lung cancer [24–27], these meta-analyses only included 3–7 studies published before 2018. Some recently published studies have not been included [22, 23]. Moreover, the potential influences of study characteristics on this association, such as category and stage of lung cancer, timing of BB use, category of BB, and smoking status of the patients, were rarely investigated. Therefore, this updated meta-analysis was performed to provide a systematic evaluation of the association between BB use and survival of lung cancer and explore the potential influences of above study characteristics on the outcome.

Methods

The design, implementation, and report of the meta-analysis was in accordance with the MOOSE (Meta-analysis of Observational Studies in Epidemiology) [28] and Cochrane’s Handbook [29] guidelines.

Literature search

Electronic databases of PubMed, Embase, and the Cochrane’s Library were searched using the combination of the following terms: (1) "adrenergic beta antagonist" OR "beta blockers" OR "beta antagonist" OR "beta adrenoreceptor antagonist" OR "beta adrenergic receptor antagonist" OR "beta adrenergic blocking agent" OR "adrenergic beta-1 receptor antagonists" OR "acebutolol" OR "alprenolol" OR "atenolol" OR "betaxolol" OR "bisoprolol" OR "bunolol" OR "bupranolol" OR "Bucindolol" OR "carteolol" OR "celiprolol" OR "Carvedilol" OR "dihydroalprenolol" OR "esmolol" OR "iodocyanopindolol" OR "labetalol" OR "levobunolol" OR "metipranolol" OR "metoprolol" OR "nadolol" OR "Nebivolol" OR "oxprenolol" OR "penbutolol" OR "practolol" OR "pindolol" OR "propranolol" OR "sotalol" OR "timolol"; (2) "lung cancer"; and (3) "survival" OR "prognosis" OR "mortality" OR "recurrence" OR "recurrent" OR "death" OR "metastasis" OR "progression" OR "hazard ratio" OR "surgery" OR "operation" OR "risk". We expanded the search terms regarding the outcomes of the patients to avoid missing of potential related studies. The search was limited to human studies published in English or Chinese. The reference lists of original and review articles were also analyzed manually. The final literature search was performed on January 15, 2020.

Study selection

Studies were included if they met the following criteria: (1) published as full-length article; (2) designed as studies with longitudinal follow-up, such as randomized controlled trials (RCTs), cohort studies, nested case-control studies, and post-hoc analyses of RCTs, with a minimal follow-up duration of one year; (3) included patients with lung cancer; (4) compared the survival outcome between users and non-users of BB with lung cancer; (5) documented the incidence of overall survival (OS) during follow-up; and (6) reported the adjusted hazard ratios (HRs, at least adjusted for age and gender) and their corresponding 95% confidence intervals (CIs) for the above outcomes in users and non-users of BB with lung cancer. Reviews, editorials, preclinical studies, cross-sectional studies, conference abstracts were excluded.

Data extracting and quality evaluation

Literature search, data extraction, and study quality assessment were independently performed by two authors according to the predefined inclusion criteria. If inconsistency occurred, discussion with the corresponding author was suggested to resolve these issues. The following data were extracted: (1) name of the first author, publication year, study location, and study design; (2) characteristics and number of patients with lung cancer, mean age, proportion of male, cancer stage, definition of BB use, and follow-up duration; and (3) outcomes reported, and variables adjusted when presenting the HRs. The quality of observational study was evaluated using the Newcastle-Ottawa Scale (NOS) [30]. This scale ranges from 1 to 9 stars and judges the quality of each study regarding three aspects: selection of the study groups; the comparability of the groups; and the ascertainment of the outcome of interest.

Statistical analyses

The association between BB use and survival outcomes in lung cancer patients was measured by adjusted HRs. To stabilize its variance and normalized the distribution, HR data and its corresponding stand error (SE) from each study was logarithmically transformed [29]. The Cochrane’s Q test was performed to evaluate the heterogeneity among the include cohort studies [29, 31], and the I2 statistic was also calculated. A significant heterogeneity was considered if I2 > 50%. A random effect model was used to pool the results since this model has been indicated to incorporate the potential heterogeneity of the included studies and therefore could provide a more generalized result. Sensitivity analysis by omitting one study at a time was performed to evaluate the stability of the results [29]. Predefined stratified analyses were performed to evaluate the potential influences of study characteristics on the outcomes, including categories of lung cancer, tumor stage, with and without of surgical resection, timing of BB use, categories of BB (selective [SBB] or non-selective BB [NSBB]), and with or without of adjustment of smoking status when presenting the results [32]. We defined BB use as before or after diagnosis of lung cancer according to the time when the patients started using of the medication. Potential publication bias was assessed by visual inspection of the symmetry of the funnel plots, complemented with the Egger regression test [33]. The RevMan (Version 5.1; Cochrane Collaboration, Oxford, UK) and STATA software were used for the statistics.

Results

Literature search

The flowchart of database search was shown in Fig 1. Briefly, 922 studies were obtained from database search, and 898 of them were excluded primarily because they were irrelevance to the aim of the study. For the remaining 24 potential relevant studies that underwent full-text review, 14 were further excluded because three of them did not include lung cancer patients, four did not report survival outcome, one included overlapped patients of other studies, three did not report multivariate adjusted data, and the other three were abstracts of already included studies. Finally, ten studies were included [14–23].

Fig 1. Flowchart of database search and study inclusion.

Fig 1

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Study characteristics and quality

Overall, this meta-analysis included ten retrospective cohort studies [14–23] with 30870 patients with lung cancer. No RCT was identified. The characteristics of the included cohorts were shown in Table 1. These studies were published between 2011 and 2020, and performed in Europe, North America, and Asia. Five studies included patients with NSCLC [15, 17, 18, 21, 23], while the remaining five included both NSCLC and SCLC [14, 16, 19, 20, 22]. The mean ages of the included patients varied between 56 and 74 years, with proportions of male varying from 50 to 95%. Users of BB were defined as BB use prior or after the diagnosis of lung cancer. The mean follow-up durations varied from 1.6 to 6.5 years. Potential confounding factors, including age, cancer stage at diagnosis, treatments, comorbidities and concurrent medications were adjusted to a varying degree in the included studies. The qualities of the included follow-up studies were generally good, with the NOS ranging from seven to nine points (Table 2).

Table 1. Characteristics of the included patients.

Study Country Design Patient characteristics Sample size Mean age Male Stages Definition of BB use Follow-up duration Outcomes reported Outcome validation Variables adjusted NOS
years % years
Shah 2011 UK RC Patients with lung cancer 436 NR NR I-IV BB use within 1y prior to the diagnosis of lung cancer 4.8 OS Medical records Age, gender, smoking status, concurrent medications, and national region 7
Aydiner 2013 Turkey RC Patients with metastatic NSCLC 107 61.0 94.4 IV BB use after the diagnosis of lung cancer 1.5 OS Medical records Age, gender, performance status, histologic subtype, smoking status, comorbidities, and concurrent medications 7
Wang 2013 the US RC Patients with NSCLC Treated with definitive radiation therapy 722 65.0 55.0 I-III BB use after the diagnosis of lung cancer 3.7 DMFS, DFS, and OS Medical records Age, gender, KPS, clinical stage, tumor histology, use of concurrent chemotherapy, radiation dose, gross tumor volume, comorbidities, and aspirin 9
Holmes 2013 Canada RC Patients with lung cancer 4241 71.0 52.3 I-IV BB use within 1y prior to the diagnosis of lung cancer 4.2 OS Medical records Age, gender, tumor stage, history of cancer, and area of residence 7
Cata 2014 the US RC Patients with NSCLC who underwent resection 435 NR 52.4 I-IIIa BB use after the diagnosis of lung cancer 4.4 DFS, and OS Medical records Age, gender, tumor stage, BMI, smoking status, preoperative and postoperative radiation, thoracotomy, perioperative blood transfusions, and comorbidities 8
Springate 2015 UK RC Patients with lung cancer 1326 NR 55.3 I-IV BB use within 1y prior to the diagnosis of lung cancer 3.2 OS Medical records Age, gender, smoking status, concurrent medications, and national region 7
Yang 2017 China RC Patients undergoing chemoradiotherapy with inoperable stage III NSCLC 606 56.7 88.6 III BB use after the diagnosis of lung cancer 1.8 OS Medical records Age, gender, smoking status, alcohol intake, tumor stage, tumor pathology, and chemotherapy 7
Weberpals 2017 Germany RC Patients with lung cancer 2500 70.4 71.9 I-IV BB use within 1y prior to or after the diagnosis of lung cancer 6.5 OS Medical records Age, gender, year of diagnosis, socio-economic status, comorbidities, cancer treatment, best supportive care, cancer stage, histology, previous cancer, concurrent medications 9
Musselma 2018 Canada RC Patients with lung cancer who underwent resection 2068 73.7 54.5 I-III BB use within 1y prior to the diagnosis of lung cancer 3.6 OS Medical records Age, gender, socioeconomic status and CCI 6
Udumyan 2020 Sweden RC Patients with NSCLC 18429 69.1 50.8 I-IV BB use within 1y prior to the diagnosis of lung cancer 1.6 OS Medical records Age, gender, tumor history, tumor stage, education, marital status, region of residence, comorbidities and concurrent medications 9
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BB, beta-blocker; NOS, Newcastle-Ottawa Scale; UK, United Kingdom; US, United States; RC, retrospective cohort; NSCLC, non-small cell lung cancer; NR, not reported; OS, overall survival; DFS, disease-free survival; DMFS, distant metastasis-free survival; KPS, Karnofsky Performance Score; CCI, Charlson Comorbidity Index; BMI, body mass index.

Table 2. Details of quality evaluation for the included studies via the Newcastle-Ottawa Scale.

Study Representativeness of the exposed cohort Selection of the non-exposed cohort Ascertainment of exposure Outcome not present at baseline Control for age and gender Control for other confounding factors Assessment of outcome Enough long follow-up duration Adequacy of follow-up of cohorts Total
Shah 2011 1 1 1 1 1 0 1 1 1 8
Aydiner 2013 0 1 1 1 1 1 1 1 1 8
Wang 2013 1 1 1 1 1 1 1 1 1 9
Holmes 2013 1 1 1 1 1 0 1 1 1 8
Cata 2014 0 1 1 1 1 1 1 1 1 8
Springate 2015 1 1 1 1 1 0 1 1 1 8
Yang 2017 0 1 1 1 1 1 1 1 1 8
Weberpals 2017 1 1 1 1 1 1 1 1 1 9
Musselma 2018 0 1 1 1 1 0 1 1 1 7
Udumyan 2020 1 1 1 1 1 1 1 1 1 9
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Overall meta-analysis

Pooling the results of ten included retrospective cohort studies showed that BB use was not associated with significantly affected OS in lung cancer (adjusted HR = 1.02, 95% CI: 0.98 to 1.06, p = 0.33; Fig 2) with moderate heterogeneity (I2 = 29%). Sensitivity analysis by omitting one study at a time showed similar results (adjusted HR: 1.01~1.02, p all > 0.05).

Fig 2. Funnel plots for the meta-analysis of overall association between BB use and OS of lung cancer.

Fig 2

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Stratified analyses

Results of stratified analyses showed that BB use was not associated with significantly affected OS in patients with NSCLC (adjusted HR = 0.97, p = 0.55), SCLC (adjusted HR = 1.02, p = 0.77), or mixed categories (adjusted HR = 1.03, p = 0.09; Fig 3), in patients with stage I-II (adjusted HR = 0.98, p = 0.73) or stage IV lung cancer (adjusted HR = 1.07, p = 0.43; Fig 4), in patients who received surgical resection (adjusted HR = 1.08, p = 0.38; Fig 5), in patients using BB prior (adjusted HR = 1.02, p = 0.13) or after the diagnosis of lung cancer (adjusted HR = 0.96, p = 0.66; Fig 6), in patients using SBB (adjusted HR = 1.02, p = 0.51; Fig 7), and in studies with (adjusted HR = 1.07, p = 0.21) or without the adjustment of smoking status (adjusted HR = 1.01, p = 0.59; Fig 8). In addition, BB use was associated with improved OS in stage III lung cancer (HR = 0.91, 95% CI: 0.85 to 0.98, p = 0.02; Fig 4) and in patients who did not receive surgery (HR = 0.78, 95% CI: 0.64 to 0.96, p = 0.02; Fig 5), while use of non-selective BB seemed to be associated with worse OS in lung cancer patients (HR = 1.14, 95% CI: 1.01 to 1.28, p = 0.03; Fig 7).

Fig 3. Stratified analyses for the meta-analysis of the association between BB use and OS of lung cancer according to the category of lung cancer.

Fig 3

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Fig 4. Stratified analyses for the meta-analysis of the association between BB use and OS of lung cancer according to the stage of the tumor.

Fig 4

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Fig 5. Stratified analyses for the meta-analysis of the association between BB use and OS of lung cancer according to whether surgical resection was performed.

Fig 5

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Fig 6. Stratified analyses for the meta-analysis of the association between BB use and OS of lung cancer according to the timing of BB use.

Fig 6

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Fig 7. Stratified analyses for the meta-analysis of the association between BB use and OS of lung cancer according to the category of BB.

Fig 7

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Fig 8. Stratified analyses for the meta-analysis of the association between BB use and OS of lung cancer according to whether smoking status was adjusted.

Fig 8

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Publication bias

The funnel plots for the association between BB and OS of lung cancer were shown in Fig 9. The plots were symmetrical on visual inspection, suggesting low risks of publication bias. Results of Egger’s regression tests also showed similar results (p = 0.627).

Fig 9. Funnel plots for the meta-analysis of overall association between BB use and OS of lung cancer.

Fig 9

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Discussion

In this meta-analysis of observational studies, we found that BB use was not significantly associated with improved OS in patients with lung cancer. Subsequently, results of comprehensive stratified analyses showed consistent results in patients with NSCLC or SCLC, in studies with BB use before or after the diagnosis of lung cancer, and in studies with or without adjustment of smoking. Limited evidence from subgroups of 2~4 studies showed that use of BB might be associated with improved OS in patients with stage III lung cancer and in patients without surgery resection, while use of non-selective BB might be associated with worse OS. Taken together, although effects of BB in certain subgroups may be significant, current evidence from retrospective cohort studies did not show a significant association between BB use and improved OS in patients with lung cancer. However, in view of the promising results in preclinical studies and the potential limitations of retrospective cohort studies, large-scale prospective cohort studies or even RCTs are needed to validate the potential influence of BB use on survival in patients with lung cancer.

Although four meta-analyses have been published previously regarding the association between BB use and survival in patients with lung cancer, these meta-analyses were based on only 3–7 studies published before 2018, mostly focusing on patients with various malignancies rather than lung cancer patients only [24–27]. Overall, results of this updated meta-analysis were consistent with findings of the previous meta-analyses, which did not show that BB use was significantly associated with improved OS in patients with lung cancer. However, our study has the following strengths as compared with previous meta-analyses. Firstly, unlike most of the previous meta-analyses which focused on the influence of BB use on survival in patients with various cancers [24–26, 34], we included updated observational studies evaluating the association between BB use and OS only in lung cancer patients. A total of 10 studies with 30870 patients were included, which accounts for a much larger sample size than previous meta-analyses. Secondly, only studies with multivariate analyses were included in this meta-analysis. Accordingly, unlike previous meta-analyses which also included studies with univariate analyses [24–26, 34], the finding of this meta-analysis was minimally affected by potential confounding factors as seen in studies based on univariate analyses. Thirdly, the stability of the finding of the meta-analysis was approved by the results of sensitivity analyses, which showed that the overall finding of the meta-analysis was not affected by either of the included studies. Fourthly, the relatively large number of included studies in the current meta-analysis compared to the previous ones enabled us to perform comprehensive subgroup analyses, which were rarely performed in previous meta-analyses [24–27, 34]. Results of subgroup analyses showed that BB use was not associated with significantly affected OS of lung cancer in patients with NSCLC or SCLC, in studies with BB use before or after the diagnosis of lung cancer, and in studies with or without adjustment of smoking, which were consistent with the results of main analysis. Moreover, subgroup analyses also showed that use of BB might be associated with improved OS in patients with stage III lung cancer and in patients without surgery resection, while use of non-selective BB might be associated with worse OS. These findings may have implications for design of subsequent prospective cohort studies or RCTs, and studies focusing on these subgroups may be considered.

Preclinical studies generally showed that activation of beta adrenergic receptor axis, particularly via beta2 adrenergic receptor is implicated in the pathogenesis and progression of lung cancer via effects on apoptosis, proliferation, angiogenesis, and migration [8]. However, these early studies were mostly performed in pulmonary adenocarcinoma cell lines [35], and subsequent analyses showed that the expression of beta adrenergic receptor may be differently expressed in different histological type of lung cancer, and the response of these cancer cells to the beta adrenergic signal may be different [36]. Lung cancer is a histopathologically heterogeneous disease. However, most of the previous studies categorized lung cancer broadly into SCLC and NSCLC rather than into specific histological type, which may explain the inconsistent results of the included studies. Our subgroup analyses which showed benefits of BB in certain subgroups (stage III lung cancer and those without surgery resection) may also be related to the heterogeneous pathological type included in these subgroups. Since surgical resection is not generally considered as standard of care for later stage patients with lung cancer, results of these subgroup analyses may reflect the potential adverse interaction of BB with treatment strategies other than surgery in these patients. Indeed, an early study including 107 patients with metastatic NSCLC receiving chemotherapy showed that BB use was associated with improved progression-free survival [15]. In addition, a recent retrospective study also showed that BB use was associated with improved prognosis in NSCLC patients that received immune checkpoint inhibitors [37]. Moreover, we found that use of non-selective BB might be associated with worse OS, which seems to be paradoxical to the previous finding from preclinical studies that beta2 adrenergic receptor signal is the main pathway involved in cancer progression. The potential explanation for this paradox remains unknown at current stage. However, a previous pooled analysis with individual patient data showed use of propranolol or NSBB was not associated with improved survival in breast cancer [38], which is also not in consistent with the finding of preclinical studies that propranolol inhibits several pathways involved in breast cancer progression and metastasis. Moreover, preclinical studies have shown that beta-adrenergic agonists may be associated with inhibition of squamous cell growth [35], highlighting the potential diverging association between cancer cell proliferation and some BBs. It has to be mentioned that for most of the included studies, SBB were mainly prescribed (> 80%), and the patients using NSBB were limited. Therefore, the influence of NSBB on survival in lung cancer should better be investigated in large-scale prospective studies or RCTs.

In contrast to the negative finding of this meta-analysis and most of the previous retrospective cohort studies, some recently published small scale studies showed potential benefits of BB on survival in lung cancer patients. In a retrospective study with 77 patients of stage IIIa NSCLC treated with neoadjuvant chemoradiation and subsequent surgery, BB users were associated with a trend of improved OS at 1 year compared with the non-users in univariate analysis (p = 0.08) [39]. Another study with 57 lung cancer patients showed that perioperative intravenous administration of an ultra-short acting SBB landiolol prolonged relapse-free survival in these patients [40], and a phase III RCT has been started accordingly [41]. Results of future prospective studies and RCTs are expected to provide more reliable evidence regarding the association between BB use and OS in patients with lung cancer, preferably according in different histopathological type.

Our study has limitations which should be noticed when interpreting the results. Firstly, only retrospective cohort studies were included. Due to the inherited limitations of retrospective cohort studies, such as recall bias, results of our meta-analysis should be validated in prospective studies. Secondly, patients taking beta blockers prior to their lung cancer diagnosis were likely to have other comorbid conditions that may increase their mortality risks. Typically, BBs are prescribed for patients with cardiovascular disorders, who may also have concurrent medications such as aspirin and statins, which have also been suggested to affect the survival in patients with lung cancer [42]. Although comorbidities and concurrent medications have been generally adjusted among the included studies, these factors may confound the relationship between BB and survival in these patients. Thirdly, since of our study is a meta-analysis based on data of study level, we were unable to provide subgroup data according to smoking history, family history of lung cancer prevalence, or genetic background of individually included patients. We have acknowledged these as potential limitations, which should be considered in designing of future studies. Moreover, although data of adjusted HR were pooled, we could not exclude the chance that there remain residual factors which may confound the association between BB use and OS in lung cancer, such as lung cancer patients with different histopathological type. Future studies are needed for further investigation. In addition, studies included in subgroups for stratified analyses are limited. Therefore, results of stratified analyses should be interpreted with caution. Finally, influences of study characteristics, such as gender and ethnicity of the patients, cancer treatments, comorbidities, and concurrent medications on the outcome could not be evaluated due to these data were rarely reported in the included studies. Further studies are warranted.

Conclusion

In conclusion, this meta-analysis based on retrospective studies failed to show a significant association between BB use and improved OS in lung cancer patients. Considering the limitations of retrospective studies and generally promising results in preclinical studies, qualified prospective studies and RCTs are needed to investigate the influence of BB use on clinical outcome in lung cancer patients.

Supporting information

S1 Checklist

(DOC)

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Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

References

  • 1.Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. Epub 2015/02/06. 10.3322/caac.21262 . [DOI] [PubMed] [Google Scholar]
  • 2.Torre LA, Siegel RL, Ward EM, Jemal A. Global Cancer Incidence and Mortality Rates and Trends—An Update. Cancer Epidemiol Biomarkers Prev. 2016;25(1):16–27. Epub 2015/12/17. 10.1158/1055-9965.EPI-15-0578 1055-9965.EPI-15-0578 [pii]. . [DOI] [PubMed] [Google Scholar]
  • 3.Schneider BJ, Ismaila N, Altorki N. Lung Cancer Surveillance After Definitive Curative-Intent Therapy: ASCO Guideline Summary. JCO Oncol Pract. 2020;16(2):83–6. Epub 2020/02/12. 10.1200/JOP.19.00722 . [DOI] [PubMed] [Google Scholar]
  • 4.Kalemkerian GP, Loo BW, Akerley W, Attia A, Bassetti M, Boumber Y, et al. NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018. J Natl Compr Canc Netw. 2018;16(10):1171–82. Epub 2018/10/17. 10.6004/jnccn.2018.0079 . [DOI] [PubMed] [Google Scholar]
  • 5.Ettinger DS, Aisner DL, Wood DE, Akerley W, Bauman J, Chang JY, et al. NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 5.2018. J Natl Compr Canc Netw. 2018;16(7):807–21. Epub 2018/07/15. 10.6004/jnccn.2018.0062 . [DOI] [PubMed] [Google Scholar]
  • 6.Helminen O, Valo J, Andersen H, Lautamaki A, Vuohelainen V, Sihvo E. Real-world guideline-based treatment of lung cancer improves short- and long-term outcomes and resection rate: A population-based study. Lung Cancer. 2020;140:1–7. Epub 2019/12/16. S0169-5002(19)30755-X [pii] 10.1016/j.lungcan.2019.12.002 . [DOI] [PubMed] [Google Scholar]
  • 7.Jones GS, Elimian K, Baldwin DR, Hubbard RB, McKeever TM. A systematic review of survival following anti-cancer treatment for small cell lung cancer. Lung Cancer. 2020;141:44–55. Epub 2020/01/20. S0169-5002(19)30779-2 [pii]. 10.1016/j.lungcan.2019.12.015 . [DOI] [PubMed] [Google Scholar]
  • 8.Nilsson MB, Le X, Heymach JV. beta-Adrenergic Signaling in Lung Cancer: A Potential Role for Beta-Blockers. J Neuroimmune Pharmacol. 2019. Epub 2019/12/13. 10.1007/s11481-019-09891-w . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Coelho M, Soares-Silva C, Brandao D, Marino F, Cosentino M, Ribeiro L. beta-Adrenergic modulation of cancer cell proliferation: available evidence and clinical perspectives. J Cancer Res Clin Oncol. 2017;143(2):275–91. Epub 2016/10/07. 10.1007/s00432-016-2278-1 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Wang W, Cao X. Beta-Adrenergic Signaling in Tumor Immunology and Immunotherapy. Crit Rev Immunol. 2019;39(2):93–103. Epub 2019/11/05. 10.1615/CritRevImmunol.2019031188 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Akbar S, Alsharidah MS. Are beta blockers new potential anticancer agents? Asian Pac J Cancer Prev. 2014;15(22):9567–74. Epub 2014/12/19. 10.7314/apjcp.2014.15.22.9567 . [DOI] [PubMed] [Google Scholar]
  • 12.Thiele M, Albillos A, Abazi R, Wiest R, Gluud LL, Krag A. Non-selective beta-blockers may reduce risk of hepatocellular carcinoma: a meta-analysis of randomized trials. Liver Int. 2015;35(8):2009–16. Epub 2015/01/13. 10.1111/liv.12782 . [DOI] [PubMed] [Google Scholar]
  • 13.Lu H, Liu X, Guo F, Tan S, Wang G, Liu H, et al. Impact of beta-blockers on prostate cancer mortality: a meta-analysis of 16,825 patients. Onco Targets Ther. 2015;8:985–90. Epub 2015/05/23. 10.2147/OTT.S78836 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.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(1):157–61. Epub 2011/04/02. 10.1111/j.1365-2125.2011.03980.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.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(10):6109–14. Epub 2013/12/03. 10.7314/apjcp.2013.14.10.6109 . [DOI] [PubMed] [Google Scholar]
  • 16.Holmes S, Griffith EJ, Musto G, Minuk GY. Antihypertensive medications and survival in patients with cancer: a population-based retrospective cohort study. Cancer Epidemiol. 2013;37(6):881–5. Epub 2013/10/01. 10.1016/j.canep.2013.09.001 . [DOI] [PubMed] [Google Scholar]
  • 17.Wang HM, Liao ZX, Komaki R, Welsh JW, O’Reilly MS, Chang JY, 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(5):1312–9. Epub 2013/01/10. 10.1093/annonc/mds616 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Cata JP, Villarreal J, Keerty D, Thakar DR, Liu DD, Sood AK, et al. Perioperative beta-blocker use and survival in lung cancer patients. J Clin Anesth. 2014;26(2):106–17. Epub 2014/02/01. 10.1016/j.jclinane.2013.10.004 . [DOI] [PubMed] [Google Scholar]
  • 19.Springate DA, Ashcroft DM, Kontopantelis E, Doran T, Ryan R, Reeves D. Can analyses of electronic patient records be independently and externally validated? Study 2—the effect of beta-adrenoceptor blocker therapy on cancer survival: a retrospective cohort study. BMJ Open. 2015;5(4):e007299 Epub 2015/04/15. 10.1136/bmjopen-2014-007299 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Weberpals J, Jansen L, Haefeli WE, Hoffmeister M, Wolkewitz M, Herk-Sukel M, et al. Pre- and post-diagnostic beta-blocker use and lung cancer survival: A population-based cohort study. Sci Rep. 2017;7(1):2911 Epub 2017/06/08. 10.1038/s41598-017-02913-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Yang P, Deng W, Han Y, Shi Y, Xu T, Shi J, et al. Analysis of the correlation among hypertension, the intake of beta-blockers, and overall survival outcome in patients undergoing chemoradiotherapy with inoperable stage III non-small cell lung cancer. Am J Cancer Res. 2017;7(4):946–54. Epub 2017/05/05. [PMC free article] [PubMed] [Google Scholar]
  • 22.Musselman RP, Bennett S, Li W, Mamdani M, Gomes T, van Walraven C, et al. Association between perioperative beta blocker use and cancer survival following surgical resection. Eur J Surg Oncol. 2018;44(8):1164–9. Epub 2018/06/03. S0748-7983(18)31066-7 [pii]. 10.1016/j.ejso.2018.05.012 . [DOI] [PubMed] [Google Scholar]
  • 23.Udumyan R, Montgomery S, Fang F, Valdimarsdottir U, Hardardottir H, Ekbom A, et al. Beta-Blocker Use and Lung Cancer Mortality in a Nationwide Cohort Study of Patients with Primary Non-Small Cell Lung Cancer. Cancer Epidemiol Biomarkers Prev. 2020;29(1):119–26. Epub 2019/10/24. 10.1158/1055-9965.EPI-19-0710 . [DOI] [PubMed] [Google Scholar]
  • 24.Zhong S, Yu D, Zhang X, Chen X, Yang S, Tang J, et al. beta-Blocker use and mortality in cancer patients: systematic review and meta-analysis of observational studies. Eur J Cancer Prev. 2016;25(5):440–8. Epub 2015/09/05. 10.1097/CEJ.0000000000000192 . [DOI] [PubMed] [Google Scholar]
  • 25.Na Z, Qiao X, Hao X, Fan L, Xiao Y, Shao Y, et al. The effects of beta-blocker use on cancer prognosis: a meta-analysis based on 319,006 patients. Onco Targets Ther. 2018;11:4913–44. Epub 2018/09/04. 10.2147/OTT.S167422 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Yap A, Lopez-Olivo MA, Dubowitz J, Pratt G, Hiller J, Gottumukkala V, et al. Effect of beta-blockers on cancer recurrence and survival: a meta-analysis of epidemiological and perioperative studies. Br J Anaesth. 2018;121(1):45–57. Epub 2018/06/25. S0007-0912(18)30281-2 [pii]. 10.1016/j.bja.2018.03.024 . [DOI] [PubMed] [Google Scholar]
  • 27.Coelho M, Squizzato A, Cassina N, Marino F, Ribeiro LV, Cosentino M. Effect of beta-blockers on survival of lung cancer patients: a systematic review and meta-analysis. Eur J Cancer Prev. 2019. Epub 2019/10/15. 10.1097/CEJ.0000000000000544 . [DOI] [PubMed] [Google Scholar]
  • 28.Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008–12. Epub 2000/05/02. jst00003 [pii]. 10.1001/jama.283.15.2008 . [DOI] [PubMed] [Google Scholar]
  • 29.Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration. 2011;www.cochranehandbook.org. [Google Scholar]
  • 30.Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2010;http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. [Google Scholar]
  • 31.Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58. Epub 2002/07/12. 10.1002/sim.1186 . [DOI] [PubMed] [Google Scholar]
  • 32.Chuang SC, Lee YC, Wu GJ, Straif K, Hashibe M. Alcohol consumption and liver cancer risk: a meta-analysis. Cancer Causes Control. 2015;26(9):1205–31. Epub 2015/07/03. 10.1007/s10552-015-0615-3 . [DOI] [PubMed] [Google Scholar]
  • 33.Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34. Epub 1997/10/06. 10.1136/bmj.315.7109.629 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.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;47:1–11. Epub 2016/05/18. 10.1016/j.ctrv.2016.04.004 . [DOI] [PubMed] [Google Scholar]
  • 35.Schuller HM, Al-Wadei HA. Beta-adrenergic signaling in the development and progression of pulmonary and pancreatic adenocarcinoma. Curr Cancer Ther Rev. 2012;8(2):116–27. Epub 2013/06/29. 10.2174/157339412800675351 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Rains SL, Amaya CN, Bryan BA. Beta-adrenergic receptors are expressed across diverse cancers. Oncoscience. 2017;4(7–8):95–105. Epub 2017/10/03. 10.18632/oncoscience.357 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Oh MS, Guzner A, Wainwright DA, Mohindra NA, Chae YK, Behdad A, et al. The Impact of Beta Blockers on Survival Outcomes in Patients With Non-small-cell Lung Cancer Treated With Immune Checkpoint Inhibitors. Clin Lung Cancer. 2020. Epub 2020/09/10. S1525-7304(20)30238-2 [pii]. 10.1016/j.cllc.2020.07.016 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Cardwell CR, Pottegard A, Vaes E, Garmo H, Murray LJ, Brown C, et al. Propranolol and survival from breast cancer: a pooled analysis of European breast cancer cohorts. Breast Cancer Res. 2016;18(1):119 Epub 2016/12/03. 10.1186/s13058-016-0782-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Chaudhary KR, Yan SX, Heilbroner SP, Sonett JR, Stoopler MB, Shu C, et al. Effects of beta-Adrenergic Antagonists on Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer. J Clin Med. 2019;8(5). Epub 2019/05/01. E575 [pii] [pii]. 10.3390/jcm8050575 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Sakamoto A, Yagi K, Okamura T, Harada T, Usuda J. Perioperative Administration of an Intravenous Beta-Blocker Landiolol Hydrochloride in Patients with Lung Cancer: A Japanese Retrospective Exploratory Clinical Study. Sci Rep. 2019;9(1):5217 Epub 2019/03/28. 10.1038/s41598-019-41520-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Yamamoto H, Hamasaki T, Onda K, Nojiri T, Aragaki M, Horie N, et al. Landiolol, an ultra-short acting beta-1 blocker, for preventing postoperative lung cancer recurrence: study protocol for a phase III, multicenter randomized trial with two parallel groups of patients. Trials. 2019;20(1):715 Epub 2019/12/13. 10.1186/s13063-019-3904-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Xia DK, Hu ZG, Tian YF, Zeng FJ. Statin use and prognosis of lung cancer: a systematic review and meta-analysis of observational studies and randomized controlled trials. Drug Des Devel Ther. 2019;13:405–22. Epub 2019/02/19. 10.2147/DDDT.S187690 [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Richard Hodge

8 Oct 2020

PONE-D-20-11931

Beta-blocker and survival in patients with lung cancer: a meta-analysis

PLOS ONE

Dear Dr. Zuo,

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors conducts a meta-analysis of 10 studies in order to assess whether there is an association between use of beta blockers and survival in patients with lung cancer. Previous research has hypothesized that use of beta-blockers may be protective for lung cancer patients, but results have been inconsistent. This manuscript aimed to synthesize available studies to provide an updated analysis, including a broader set of studies than prior analyses.

Major Comments:

1. The authors mention multiple other meta analyses looking at this same topic, but there is no discussion of whether the results from this study were consistent with previous meta analyses. Additionally, in the discussion, the authors say that previous meta analyses did not focus on lung cancer. If so, that should be highlighted when discussing how this study is different from prior ones.

2. The authors focused their analysis on survival, however the search terms include outcomes of recurrence, metastasis, progression, surgery, and operation. Please explain why these outcomes were included in the search terms and whether analyses of these outcomes was undertaken.

3. In the section about “Data extracting and quality evaluation”, the authors mention covariates included in the adjustment of RRs. Please clarify whether the outcomes reported were reported as risk ratios or hazard ratios.

4. The methods suggest that included studies needed to have a minimum follow up of one year, however, Table 2 indicates that not all studies had a sufficiently long follow up. Please clarify.

5. Are the authors defining BB use as before or after diagnosis of lung cancer to mean when they started using beta-blockers? Otherwise, it would seem that in figure 4, these are not mutually exclusive categories (ie: patients could have started taking BB before diagnosis, and continued after diagnosis).

6. The results suggest that there may be a benefit to BB in stage III cancers, and those without surgical resection. As surgical resection is not generally considered standard of care for later stage patients (but is for earlier stage patients), the interaction of other therapies besides surgery BB may be an interesting discussion point.

7. Patients taking beta blockers prior to their lung cancer diagnosis likely have other comorb conditions that may put them at higher risk of mortality. This may confound the relationship between beta-blockers and survival in these patients. This should be more clearly defined and discussed.

8. In the discussion of promising studies (page 14-15): why were these studies were not included in the meta analysis?

Minor Comments:

1. The paper could benefit from English language editing

2. Please include a footnote in the tables for abbreviations used

3. It may be beneficial to split figures 3 and 4, as they are almost impossible to read without zooming in.

Reviewer #2: As author concluded that BB failed to show OS in lung cancer patients, I would encourage author to have specific data on patients regarding smoking history, family history of lung cancer prevalence, environmental effect of subgroup of patients and more importantly genetic background such as mutation analysis data which could support the claim in sub groups.

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2021 Feb 16;16(2):e0245773. doi: 10.1371/journal.pone.0245773.r002

Author response to Decision Letter 0

8 Dec 2020

Response to Reviewer 1

Major Comments:

1. The authors mention multiple other meta analyses looking at this same topic, but there is no discussion of whether the results from this study were consistent with previous meta analyses. Additionally, in the discussion, the authors say that previous meta analyses did not focus on lung cancer. If so, that should be highlighted when discussing how this study is different from prior ones.

Authors’ response: Thanks for your comments. We have compared results of current meta-analysis with those of previous meta-analyses. Moreover, the strengths of current meta-analysis, compared to the previous ones, have also been discussed in the second paragraph of Discussion section of the revised manuscript.

2. The authors focused their analysis on survival, however the search terms include outcomes of recurrence, metastasis, progression, surgery, and operation. Please explain why these outcomes were included in the search terms and whether analyses of these outcomes was undertaken.

Authors’ response: Thanks for your comments. We expanded the search terms regarding the outcomes of the patients to avoid missing of potential related studies. This has been clarified in the revised methods section. Analyses regarding these outcomes were not performed because this meta-analysis focused on the survival outcomes.

3. In the section about “Data extracting and quality evaluation”, the authors mention covariates included in the adjustment of RRs. Please clarify whether the outcomes reported were reported as risk ratios or hazard ratios.

Authors’ response: Thanks for your comments. It should be “HR”, which has been corrected in the revised manuscript. We apologize for the typo.

4. The methods suggest that included studies needed to have a minimum follow up of one year, however, Table 2 indicates that not all studies had a sufficiently long follow up. Please clarify.

Authors’ response: Thanks for your comments. We have noticed the error in Table 2. We defined adequate follow up as a minimum of one year, and all of the included studies met this criterion. Table 2 has been revised according.

5. Are the authors defining BB use as before or after diagnosis of lung cancer to mean when they started using beta-blockers? Otherwise, it would seem that in figure 4, these are not mutually exclusive categories (ie: patients could have started taking BB before diagnosis, and continued after diagnosis).

Authors’ response: Thanks for your comments. Indeed, we defined BB use as before or after diagnosis of lung cancer according to the time when the patients started using of the medication. This has been clarified in the revised method section.

6. The results suggest that there may be a benefit to BB in stage III cancers, and those without surgical resection. As surgical resection is not generally considered standard of care for later stage patients (but is for earlier stage patients), the interaction of other therapies besides surgery with BB may be an interesting discussion point.

Authors’ response: Thanks for your comments. We have added some discussion regarding these subgroup analyses in the revised manuscript as “Since surgical resection is not generally considered as standard of care for later stage patients with lung cancer, results of these subgroup analyses may reflect the potential adverse interaction of BB with treatment strategies other than surgery in these patients. Indeed, an early study including 107 patients with metastatic NSCLC receiving chemotherapy showed that BB use was associated with improved progression-free survival [1]. In addition, a recent retrospective study also showed that BB use was associated with improved prognosis in NSCLC patients that received immune checkpoint inhibitors [2]”.

7. Patients taking beta blockers prior to their lung cancer diagnosis likely have other comorbid conditions that may put them at higher risk of mortality. This may confound the relationship between beta-blockers and survival in these patients. This should be more clearly defined and discussed.

Authors’ response: Thanks for your comments. We have discussed this in the limitation section of the revised manuscript as “Secondly, patients taking beta blockers prior to their lung cancer diagnosis were likely to have other comorbid conditions that may increase their mortality risks. Typically, BBs are prescribed for patients with cardiovascular disorders, who may also have concurrent medications such as statins, which have also been suggested to favorably affect the survival in patients with lung cancer [3]. Although comorbidities and concurrent medications have been generally adjusted among the included studies, these factors may confound the relationship between BB and survival in these patients”.

8. In the discussion of promising studies (page 14-15): why were these studies were not included in the meta analysis?

Authors’ response: Thanks for your comments. These studies were not included because they were univariate-analysis studies or did not report HR for overall survival.

Minor Comments:

1. The paper could benefit from English language editing

Authors’ response: Thanks for your comments. Our revised manuscript has been proofread by the Medjaden Bioscience Limited, a professional agency for language editing of scientific research paper, to improve English writing.

2. Please include a footnote in the tables for abbreviations used

Authors’ response: Thanks for your comments. A footnote for abbreviations has been embedded for Table 1, but not for Table 2 because there was not any abbreviations in Table 2.

3. It may be beneficial to split figures 3 and 4, as they are almost impossible to read without zooming in.

Authors’ response: Thanks for your comments. Figure 3 and 4 has been split accordingly as Figure 3-8 in the revised manuscript.

Reviewer #2:

As author concluded that BB failed to show OS in lung cancer patients, I would encourage author to have specific data on patients regarding smoking history, family history of lung cancer prevalence, environmental effect of subgroup of patients and more importantly genetic background such as mutation analysis data which could support the claim in sub groups.

Authors’ response: Thanks for your comments. In fact, we have performed subgroup analyses according to the adjustment of smoking status in Figure 8 of the revised manuscript, which showed that BB use was not significantly associated with improved OS of lung cancer in studies with and without the adjustment of smoking status of the patients. Since of our study is a meta-analysis based on study level, we were unable to provide subgroup data based on smoking history, family history of lung cancer prevalence, or genetic background of individually included patients. We have acknowledged these as potential limitations, which should be considered in designing of future studies. These contents have been added in the limitation section of the revised manuscript.

References

1. 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(10):6109-14. Epub 2013/12/03. doi: 10.7314/apjcp.2013.14.10.6109. PubMed PMID: 24289634.

2. Oh MS, Guzner A, Wainwright DA, Mohindra NA, Chae YK, Behdad A, et al. The Impact of Beta Blockers on Survival Outcomes in Patients With Non-small-cell Lung Cancer Treated With Immune Checkpoint Inhibitors. Clin Lung Cancer. 2020. Epub 2020/09/10. doi: S1525-7304(20)30238-2 [pii]

10.1016/j.cllc.2020.07.016. PubMed PMID: 32900613.

3. Xia DK, Hu ZG, Tian YF, Zeng FJ. Statin use and prognosis of lung cancer: a systematic review and meta-analysis of observational studies and randomized controlled trials. Drug Des Devel Ther. 2019;13:405-22. Epub 2019/02/19. doi: 10.2147/DDDT.S187690

dddt-13-405 [pii]. PubMed PMID: 30774306; PubMed Central PMCID: PMC6350654.

Decision Letter 1

Jianxin Xue

8 Jan 2021

Beta-blocker and survival in patients with lung cancer: a meta-analysis

PONE-D-20-11931R1

Dear Dr. Zuo,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Jianxin Xue

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I would like to thank the authors for this revised submission. I have a few additional comments.

1. Table 1 indicates that some studies reported disease free survival, in addition to overall survival. Were these survival outcomes used at all, or was the analysis limited to overall survival. In some places it seems like OS is the only outcome analyzed, but in some places, the authors refer to general “survival outcomes”. If only OS was extracted and analyzed, please specify. If other types of survival were included, please describe how those outcomes were combined.

2. Please define what is meant by selective and non-selective use of beta blockers.

3. Given the large number of subgroup analyses, please address the possibility of false positive/negative results.

4. Where the authors write “Since surgical resection is not generally considered as standard of

care for later stage patients with lung cancer, results of these subgroup analyses may

reflect the potential adverse interaction of BB with treatment strategies other than

surgery in these patients”, please confirm whether adverse interaction is what is meant? The results about those without surgery, along with the next sentence seem to say that research has shown BB to be associated with improved survival in people who receive no surgery/other therapies, not worse survival.

Minor Comments:

1. Figure 2 is listed in the figure legends as the funnel plot, but in the text, it is referred to as Figure 9.

Reviewer #2: Thank you for the response. For future studies please try to underline the patient genetic and environmental factors.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Acceptance letter

Jianxin Xue

2 Feb 2021

PONE-D-20-11931R1

Beta-blocker and survival in patients with lung cancer: a meta-analysis

Dear Dr. Zuo:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Jianxin Xue

Academic Editor

PLOS ONE

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