Increased Sympathetic Nervous System Impairs Prognosis in Lung Cancer Patients: A Scoping Review of Clinical Studies

Figures & data

Figure 1. Flowchart for study selection adapted from the PRISMA-ScR statement.

Table 1. Summary of methodological quality.

Study/year	Reporting	External validity	Internal validity - bias	Internal validity (selection bias)	Power	Total score	Ref.
Aydiner et al., 2013	10/11	01/03	04/07	03/06	0/1	18	[34]
Cata et al., 2014	11/11	01/03	04/07	03/06	0/1	19	[35]
Chang et al., 2020	09/11	03/03	04/07	03/06	0/1	19	[36]
Chaudhary et al., 2019	10/11	02/03	03/07	02/06	0/1	17	[37]
Coelho et al., 2019	10/11	01/03	04/07	03/06	0/1	18	[38]
Cui et al., 2019	07/11	01/03	04/07	02/06	0/1	14	[56]
Holmes et al., 2013	08/11	01/03	04/07	02/06	0/1	15	[39]
Kaira et al., 2019	09/11	02/03	04/07	02/06	0/1	17	[40]
Lin et al., 2015	09/11	03/03	04/07	02/06	0/1	18	[41]
Mei et al., 2019	08/11	01/03	05/07	02/06	0/1	16	[42]
Musselman et al., 2018	08/11	02/03	04/07	02/06	0/1	16	[43]
Numbere et al., 2015	07/11	01/03	04/07	03/06	0/1	15	[44]
Oh et al., 2020	07/11	01/03	04/07	03/06	0/1	15	[45]
Sakamoto et al., 2019	08/11	01/03	05/07	03/06	0/1	17	[46]
Shah et al., 2011	08/11	02/03	03/07	02/06	0/1	15	[47]
Shao et al., 2016	08/11	02/03	04/07	02/06	0/1	16	[48]
Udumyan et al., 2020	11/11	02/03	03/07	02/06	0/1	18	[49]
Wang et al., 2006	09/11	01/03	05/07	03/06	0/1	18	[50]
Wang et al., 2013	09/11	01/03	04/07	02/06	0/1	16	[51]
Wang et al., 2015	10/11	01/03	04/07	02/06	0/1	17	[52]
Weberpals et al., 2017	10/11	02/03	03/07	04/06	0/1	19	[17]
Yang et al., 2017	10/11	01/03	04/07	02/06	0/1	17	[17]
Yazawa et al., 2016	07/11	01/03	03/07	02/06	0/1	13	[16]
Ji et al., 2022	09/11	01/03	05/07	03/06	0/1	18	[55]

Excellent = 26 to 28; Good = 20 to 25; Fair = 15 to 19; Poor = <14.

Table 2. Summary of included studies.

Study/year	n	Mean age	Cancer type	Intervention/exposure	Comparison/control	Study design	Ref.
Cata et al., 2014	435	Not clear	NSCLC	Use of more than one β-blocker (selective and non-selective)	Non-use of β-blockers	Observational study (Cohort)	[35]
Oh et al., 2020	109	CG = 65.7 ± 12.5; Intervention = 73.7 ± 10.1	NSCLC (stage IV)	Use of more than one β-blocker (selective and non-selective)	Non-use of β-blockers	Observational study (cohort)	[44]
Weberpals et al., 2017	3340	Mean age 70 years old	NSCLC and SCLC	Use of more than one β-blocker (selective and non-selective)	Non-use of β-blockers	Observational study (cohort)	[53]
Chaudhary et al., 2019	77	Median 65 (range 41–79) years old	NSCLC (stage IIIA)	Use of more than one β-blocker ^†	Non-use of β-blockers	Non-randomized (quasi-experimental)	[37]
Aydiner et al., 2013	107	Mean age 61 (range 42–81) years old	NSCLC (with metastasis)	Use of more than one β-blocker ^†	Non-use of β-blockers	Observational study (case-control)	[34]
Shah et al., 2011	436	Between 40 to 85 years old	Not clear	Use of more than one β-blocker (selective and non-selective)	Non-use of β-blockers	Observational study (cohort)	[47]
Chang et al., 2020	4988	Not clear	NSCLC (adenocarcinoma)	Use of more than one β-blocker ^†	Non-use of β-blockers	Observational study (cohort)	[36]
Wang et al., 2013	722	Median 65 (range 34–95) years old	NSCLC	Use of more than one β-blocker (selective and non-selective)	Non-use of β-blockers	Observational study (cohort)	[51]
Holmes et al., 2013	4241	Mean age 71 ± 11 years old	Not clear	use of more than one β-blocker (selective and non-selective) ^‡	Without use of antihypertensive agent	Observational study (cohort)	[39]
Yang et al., 2017	606	Hypertension = 54.74 ± 9.283; CG = 57.18 ± 8.957 years old	NSCLC (stage III)	Use of more than one β-blocker ^†	Non-use of β-blockers	Observational study (cohort)	[54]
Wang et al., 2015	673	Median 65 (range 34 to 95)	NSCLC (stage III)	Use of more than one β-blocker ^†	Non-use of cardiac medications	Observational study (cohort)	[52]
Sakamoto et al., 2019	57	Intervention = 70.3 ± 7.5; CG = 69.1 ± 8.4	Not clear (stage I–III)	Use of selective β-blocker (landiolol hydrochloride)	Use of placebo	Observational study (cohort)	[46]
Cui et al., 2019	824	>40 years old	Not clear	Use of more than one β-blocker (selective)	Non-use of Antihypertensive Medications	Observational study (cohort)	[56]
Udumyan et al., 2020	18.429	CG = 67.8 ± 9.8; Intervention = 71.9 ± 8.3	NSCLC	Use of more than one β-blocker (selective and non-selective)	Non-use of β-blockers	Observational study (cohort)	[49]
Musselman et al., 2018	2.068	CG = 73.7 ± 4.8; Intervention = 73.7 ± 4.8	Not clear	Use of more than one β-blocker (selective and non-selective)	Non-use of β-blockers	Observational study (cohort)	[43]
Lin et al., 2015	13542	Intervention = 62.8 ± 12.8; CG = 63.1 ± 12.9	Not clear	Use of non-selective β-blocker (carvedilol)	Non-use of carvedilol	Observational study (cohort)	[41]
Numbere et al., 2015	19082	Not clear	Not clear	individuals with cancer that use more than one β-blocker (selective and non-selective)	individuals without cancer	Observational study (case-control)
Coelho et al., 2019	80	Not clear	NSCLC (40 adenocarcinoma and 40 squamous cell carcinoma (10 of each clinical stage)	tumor tissue	Surrounding non-tumor tissue	Non-randomized (quasi-experimental)	[38]
Kaira et al., 2019	105	Median 69 (range 35–88) years old	NSCLC (pulmonary pleomorphic carcinoma)	Individuals with pulmonary pleomorphic carcinoma	Different disease stages	Non-randomized (quasi-experimental)	[40]
Yazawa et al., 2016	347	Not clear	NSCLC (stage I–III)	Assessed of lymph-node dissected	Different expression levels of β2-Adrenergic receptor	Non-randomized (quasi-experimental)	[16]
Wang et al., 2006	634	Intervention = 56.6 ± 8.7; CG = 57.9 ± 9.4 years old	NSCLC (adenocarcinoma)	individuals with adenocarcinoma	individuals without cancer	Observational study (case-control)	[50]
Mei et al., 2019	600	Intervention = 57.86 ± 10.24; CG = 58.38 ± 10.65	Not clear	individuals with cancer	individuals without cancer	Observational study (case-control)	[42]
Shao et al., 2016	95 (30 control)	CG = 60.3 ± 12.8; Low risk = 55.4 ± 8.8; High risk = 59.8 ± 12.0	NSCLC (adenocarcinoma)	individuals with cancer	individuals without cancer	Non-randomized (quasi-experimental)	[48]
Ji et al., 2022	535	Not clear	NSCLC (adenocarcinoma)	Different expression levels of β2-Adrenergic receptor	Different expression levels of β2-Adrenergic receptor	Non-randomized (quasi-experimental)	[55]

† Study did not distinguish between selective and non-selective β-blockers.

‡ Use of each class of antihypertensive agent, only β-blockers were considered for analysis.

CG: Control group; Intervention/Exposure: Group that received or was exposed to a treatment; Low and high-risk: Related to pathologic risk grading in lung cancer.

Table 3. β-adrenergic outcomes.

Studies	Outcome assessed				Results				Ref.
	Survival	RFS	Mortality	Incidence	Survival	RFS	Mortality	Incidence
β-blockers without considering cancer treatments
Weberpals et al., 2017	x				-				[53]
Shah et al., 2011	x				-				[47]
Holmes et al., 2013	x				-				[39]
Yang et al., 2017	x				-				[54]
Cui et al., 2019	x	x			-	-			[56]
Udumyan et al., 2020			x				-		[49]
Lin et al., 2015				x				✓	[41]
Numbere et al., 2015				x				-	[44]
β-blockers associated with cancer treatments
Chang et al., 2020	x				✓				[36]
Chaudhary et al., 2019	x	x			✓	✓			[37]
Wang et al., 2013	x	x			✓	✓			[51]
Aydiner et al., 2013	x				✓				[34]
Oh et al., 2020	x	x			✓	✓			[45]
Wang et al., 2015	x	x			✓	✓			[52]
β-blockers during the perioperative period
Cata et al., 2014	x	x			-	-			[35]
Sakamoto et al., 2019	x	x			✓	✓			[46]
Musselman et al., 2018	x		x		-		-		[43]

RFS: Recurrence-free survival; x: Evaluation performed; ✓: Significant difference; -: No significance.

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 Pacific J. Cancer Preven. 14(10), 6109–6114 (2013).

 PubMedGoogle Scholar

Cata JP , Villarreal J , Keerty D et al. Perioperative beta-blocker use and survival in lung cancer patients. J. Clin. Anesth. 26(2), 106–117 (2014).

 PubMed Web of Science ®Google Scholar

Chang C-H , Lee C-H , Ko J-C et al. Effect of β-blocker in treatment-naïve patients with advanced lung adenocarcinoma receiving first-generation EGFR-TKIs. Front. Oncol. 10, 583529 (2020).

 PubMed Web of Science ®Google Scholar

Chaudhary KR , Yan SX , Heilbroner SP et al. Effects of β-Adrenergic antagonists on chemoradiation therapy for locally advanced non-small-cell lung cancer. J. Clin. Med. 8(5), 575 (2019).

 PubMed Web of Science ®Google Scholar

Coelho M , Imperatori A , Chiaravalli AM et al. Beta1-and beta2-adrenoceptors expression patterns in human non-small-cell lung cancer: relationship with cancer histology. J. Neuroimm. Pharmacol. 14(4), 697–708 (2019).

 PubMed Web of Science ®Google Scholar

Cui Y , Wen W , Zheng T et al. Use of antihypertensive medications and survival rates for breast, colorectal, lung, or stomach cancer. Am. J. Epidemiol. 188(8), 1512–1528 (2019).

 PubMed Web of Science ®Google Scholar

Holmes S , Griffith EJ , Musto G , Minuk GY . Antihypertensive medications and survival in patients with cancer: a population-based retrospective cohort study. Cancer Epidemiol. 37(6), 881–885 (2013).

 PubMed Web of Science ®Google Scholar

Kaira K , Kamiyoshihara M , Kawashima O et al. Prognostic impact of β2 adrenergic receptor expression in surgically resected pulmonary pleomorphic carcinoma. Anticancer Res. 39(1), 395–403 (2019).

 PubMed Web of Science ®Google Scholar

Lin C-S , Lin W-S , Lin C-L , Kao C-H . Carvedilol use is associated with reduced cancer risk: a nationwide population-based cohort study. Int. J. Cardiol. 184, 9–13 (2015).

 PubMed Web of Science ®Google Scholar

Mei L , Huang C , Wang A , Zhang X . Association between ADRB2, IL33, and IL2RB gene polymorphisms and lung cancer risk in a Chinese Han population. Internation. Immunopharmacol. 77, 105930 (2019).

 PubMed Web of Science ®Google Scholar

Musselman RP , Bennett S , Li W et al. Association between perioperative beta blocker use and cancer survival following surgical resection. Eur. J. Surg. Oncol. 44(8), 1164–1169 (2018).

 PubMed Web of Science ®Google Scholar

Numbere B , Fleming KM , Walker A , Card TR . Adrenergic blockers and the risk for common solid cancers: a case–control study. Eur. J. Cancer Prev. 26(1), 86–93 (2017).

 PubMed Web of Science ®Google Scholar

Oh MS , Guzner A , Wainwright DA 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 22(1), e57–e62 (2021).

 PubMed Web of Science ®Google Scholar

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. Scient. Rep. 9(1), 1–6 (2019).

 PubMedGoogle Scholar

Shah SM , Carey IM , Owen CG , Harris T , Dewilde S , Cook DG . Does β-adrenoceptor blocker therapy improve cancer survival? Findings from a population-based retrospective cohort study. Br. J. Clin. Pharmacol. 72(1), 157–161 (2011).

 PubMed Web of Science ®Google Scholar

Shao JX , Wang B , Yao YN , Pan ZJ , Shen Q , Zhou JY . Autonomic nervous infiltration positively correlates with pathological risk grading and poor prognosis in patients with lung adenocarcinoma. Thor. Cancer 7(5), 588–598 (2016).

 PubMed Web of Science ®Google Scholar

Udumyan R , Montgomery S , Fang F et al. β-Blocker Use and Lung Cancer Mortality in a Nationwide Cohort Study of Patients with Primary Non–Small Cell Lung Cancer. Cancer Epidemiol. Biomark. Preven. 29(1), 119–126 (2020).

 PubMed Web of Science ®Google Scholar

Wang H , Hao B , Chen X et al. Beta-2 adrenergic receptor gene (ADRB2) polymorphism and risk for lung adenocarcinoma: a case–control study in a Chinese population. Cancer Lett. 240(2), 297–305 (2006).

 PubMed Web of Science ®Google Scholar

Wang H , Liao Z , Komaki R et al. Improved survival outcomes with the incidental use of β-blockers among patients with non-small-cell lung cancer treated with definitive radiation therapy. Ann. Oncol. 24(5), 1312–1319 (2013).

 PubMed Web of Science ®Google Scholar

Wang H , Liao Z , Zhuang Y et al. Incidental receipt of cardiac medications and survival outcomes among patients with stage III non–small-cell lung cancer after definitive radiotherapy. Clin. Lung Cancer 16(2), 128–136 (2015).

 PubMed Web of Science ®Google Scholar

Torre LA , Siegel RL , Ward EM , Jemal A . Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiol. Biomarkers Prev. 25(1), 16–27 (2016).

 PubMed Web of Science ®Google Scholar

Yazawa T , Kaira K , Shimizu K et al. Prognostic significance of β2-adrenergic receptor expression in non-small-cell lung cancer. Am. J. Transl. Res. 8(11), 5059 (2016).

 PubMed Web of Science ®Google Scholar

Ji L , Xu F , Zhang J et al. ADRB2 expression predicts the clinical outcomes and is associated with immune cells infiltration in lung adenocarcinoma. Scien. Reports 12(1), 15994 (2022).

 PubMedGoogle Scholar

Weberpals J , Jansen L , Haefeli WE et al. Pre-and post-diagnostic β-blocker use and lung cancer survival: a population-based cohort study. Scient. Reports 7(1), 1–11 (2017).

 PubMedGoogle Scholar

Yang P , Deng W , Han Y et al. Analysis of the correlation among hypertension, the intake of β-blockers, and overall survival outcome in patients undergoing chemoradiotherapy with inoperable stage III non-small-cell lung cancer. Am. J. Cancer Res. 7(4), 946 (2017).

 PubMed Web of Science ®Google Scholar