International Journal of Cardiology 184 (2015) 9–13

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Carvedilol use is associated with reduced cancer risk: A nationwide population-based cohort study Chin-Sheng Lin a, Wei-Shiang Lin a, Cheng-Li Lin b,c, Chia-Hung Kao d,e,⁎ a

Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan College of Medicine, China Medical University, Taichung, Taiwan d Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan e Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan b c

a r t i c l e

i n f o

Article history: Received 30 December 2014 Received in revised form 29 January 2015 Accepted 8 February 2015 Available online 10 February 2015 Keywords: Carvedilol Cancer Beta-blocker Taiwan National Health Insurance Research Database Population-based cohort study

a b s t r a c t Background: To investigate the effect of carvedilol on the incidence of cancer in a large population-based cohort study. Methods: Data were obtained from the Taiwan National Health Insurance Research Database. The cohort study included 6771 patients who received long-term carvedilol treatment between 2000 and 2010 (carvedilol cohort) and 6771 matched controls (noncarvedilol cohort). A Cox proportional hazards model was used to evaluate the risk of cancer in the patients treated with carvedilol. Results: With the mean follow-up period of 5.17 years and 4.93 years in the carvedilol and noncarvedilol cohorts, respectively, the patients in the carvedilol cohort had a 26% reduction of cancer risk compared with those in the noncarvedilol cohort (hazard ratio [HR] = 0.74; 95% confidence interval [CI] = 0.63–0.87; p b .001). The sex-specific carvedilol to noncarvedilol relative risk was lower for both women (HR = 0.73; 95% CI = 0.56–0.94) and men (HR = 0.75; 95% CI = 0.61–0.92). Moreover, stratified by cancer site, treatment with carvedilol in the carvedilol cohort resulted in significantly lower incidence of stomach and lung cancers than in the noncarvedilol cohort. Conclusion: This nationwide population-based cohort study demonstrated that long-term treatment with carvedilol is associated with reduced upper gastrointestinal tract and lung cancer risk, indicating that carvedilol could be a potential agent in these cancers prevention. © 2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction The β-adrenergic signaling pathway mediates sympathetic nerve system-induced fight-or-flight stress responses, which is suggested to regulate the initiation and progression of cancer through several mechanisms, such as inflammation, angiogenesis, resistance to apoptosis, stimulation of tumor cell invasion, and epithelial–mesenchymal transition [1]. Previous studies have demonstrated that the use of propranolol, a nonselective β-blocker, exerts antitumor effects through antiangiogenesis, inhibition of stress-induced macrophage infiltration, and hypoxia-inducible factor 1α-mediated inhibition of vascular endothelial growth factor (VEGF) signaling [2–5]. Moreover, when combined with gemcitabine, a β-blocker is known to exert synergistic antiproliferative and apoptotic effects through inhibition of nuclear factor (NF)-κB

⁎ Corresponding author at: Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan. E-mail address: [email protected] (C.-H. Kao).

http://dx.doi.org/10.1016/j.ijcard.2015.02.015 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.

signaling [6]. These studies indicated the possible role of β-adrenergic signaling in tumor biology. Carvedilol, a nonselective β-blocker with α1 adrenoceptor blocking and potent antioxidant activity, is currently being used for the treatment of coronary artery disease (CAD), hypertension, or symptomatic heart failure [7,8]. Data from several in vitro studies have demonstrated that carvedilol exerts antiproliferative and cytotoxic effects on various human cancer cell lines [9–11]. A combination of carvedilol and imatinib mesylate revealed synergistic tumor cytotoxicity in rat glioma cells [9]. In addition, compared with other β-blockers, carvedilol exhibited the most potent antiproliferative and antiangiogenic properties in neuroblastoma cells [2]. Carvedilol enhanced response to chemotherapy with vincristine, which provided optimal survival benefits among neuroblastoma-bearing mice treated with vincristine and other β-blockers [2]. Although there is strong preclinical evidence suggesting the beneficial role of carvedilol in cancer treatment, no large population-based study has evaluated the association between carvedilol and cancer risk. Therefore, this study investigated the effect of carvedilol on the incidence of cancer in a large population-based cohort study. We used the

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C.-S. Lin et al. / International Journal of Cardiology 184 (2015) 9–13

Taiwan National Health Insurance Database for analysis and statistics, and hypothesized that treatment with carvedilol reduces the risk of cancer. We suggested that the long-term use of carvedilol is associated with reduced upper gastrointestinal tract and lung cancer risk, indicating that carvedilol could be a potential therapeutic agent in these cancers' prevention.

is issued by the government after a stringent process of verification, which involves review of medical records, images, and pathology reports by a panel of specialists and experts on the disease. The study patients were followed up from the index date until the date of cancer diagnosis, withdrawal from the NHI program, or when the database ended (December 31, 2011).

2. Methods

2.4. Statistical analysis

2.1. Data source

The distribution of demographic status and comorbidities was expressed as a frequency (percentage) or mean ± standard deviation (SD). The categorical variables were analyzed using the chi-square test, and the continuous variables of the baseline characteristics of the carvedilol and noncarvedilol cohorts were analyzed using the Student t test. The Kaplan–Meier method was employed to determine the cumulative incidence curves of cancer between the 2 cohorts, and the logrank test was conducted to examine the difference between the curves. The incidence densities were calculated for each cohort by sex, age, and type of cancer. Cox proportional hazards model stratification of the matched pairs was used to measure the effect of carvedilol on the time to cancer diagnosis. The hazard ratio (HR) is presented with 95% or 99.5% confidence interval (CI). The Bonferroni adjustment was used in multiple comparisons. All statistical analyses were performed using SAS, Version 9.3 (SAS Institute, Cary, NC, USA). Comparison results with a P value less than .05 were considered statistically significant.

The National Health Insurance (NHI) program was initiated by the Taiwanese government in 1995 to provide comprehensive health care for all residents of Taiwan. More than 99% of the 22.6 million residents of Taiwan are enrolled in this system (http://www.nhi.gov.tw/english/ index.aspx). The Bureau of National Health Insurance releases scrambled data to the National Health Research Institutes (NHRI) to establish the National Health Insurance Research Database (NHIRD). This study adopted the Longitudinal Health Insurance Database 2000 (LHID2000), a subset of one million insurants randomly selected from the NHIRD from 1996 to 2000. The LHID2000 contains medical data identified by encrypted patient numbers, including sex, date of birth, registry of medical services, diagnoses (identified based on International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] diagnostic and procedure codes), and medication prescription details. This study was approved by the Institutional Review Board of China Medical University (CMU-REC-101-012). 2.2. Sampled patients This retrospective cohort study used data extracted from the LHID2000. The current study included patients aged N 20 years for whom complete information was available with regard to age and sex and who had no history of cancer (ICD-9-CM codes 140–208) between January 1, 2000 and December 31, 2010. The patients were divided into 2 cohorts based on their carvedilol use: the carvedilol cohort included patients who had received carvedilol therapy for at least 2 years (730 d); the noncarvedilol cohort included patients who had not received carvedilol therapy before and during follow-up. The index date in the carvedilol cohort was the 730th day, and the index date in the noncarvedilol cohort (controls) was the same date as in the carvedilol cohort. Patients in the carvedilol and noncarvedilol cohorts were selected by 1:1 matching based on a propensity score [12]. The propensity score was calculated using a logistic regression to estimate the probability of the treatment assignment, based on the baseline variables including year of receiving carvedilol treatment, age, sex, Charlson comorbidity index (CCI) score and comorbidities of hypertension (ICD-9-CM codes 401–405), CAD (ICD-9-CM codes 410–414), atrial fibrillation (AF; ICD-9-CM code 427.3), supraventricular tachycardia (ICD-9-CM codes 427.0, 427.2), and palpitation (ICD-9-CM code 785.1). The C-statistic of the logistic regression model was 0.51. The carvedilol cohort comprised 6771 patients and the noncarvedilol cohort comprised 6771 patients. The cumulative censoring rate over 12 years (2000–2011) was 13.54% in the carvediolol cohort, which was slightly lower than that in the noncarvediolol cohort (17.5%). The possible reasons for the discontinuity of national health insurance include death, withdrawal of insurance, immigration, prison sentence, etc. 2.3. Outcome measurement The study outcome was a diagnosis of cancer (ICD-9-CM codes 140–195, 200–208) during the 11-year follow-up. Cancer events were identified according to the Registry of Catastrophic Illness Patient Database, which is a subset of the NHIRD. Cancer is categorized as a catastrophic illness in the NHI program and patients newly diagnosed with cancer can apply for a catastrophic illness certification. The certification

3. Results Eligible study patients included 6771 patients who used carvedilol for 2 years (carvedilol cohort) and 6771 patients who had never used carvedilol therapy, matched on the propensity score (noncarvedilol cohort or controls) (Table 1). The mean age of the patients in the carvedilol and noncarvedilol cohorts was 62.8 (± 12.8) and 63.1 (± 12.9) years, respectively. No significant differences in distribution of age, sex, CCI score, and comorbidities between the carvedilol and noncarvedilol cohorts were found. The mean follow-up period was 5.17 (SD = 2.78) and 4.93 (SD = 2.91) years in the carvedilol and noncarvedilol cohorts, respectively (data not shown). The plot of the Kaplan–Meier analysis showed that, by the end of the 11-year follow-up period, the cumulative Table 1 Demographic characteristics of study subjects among medicine in the propensity score matched sample. Carvedilol

p-value

No

Age, mean (SD)a Stratify age 20–49 50–64 65+ Gender Women Men CCI scoreb 0 1 2 3 or more Comorbidity Hypertension Coronary artery disease Atrial fibrillation Supraventricular tachycardia Palpitation a b

Yes

(n = 6771)

(n = 6771)

n

n

% 63.1

(12.9)

% 62.8

(12.8)

1132 2469 3170

(16.7) (36.5) (46.8)

1157 2479 3135

(17.1) (36.6) (46.3)

2985 3786

(44.1) (55.9)

2990 3781

(44.2) (55.8)

3868 1448 645 810

(57.1) (21.4) (9.53) (12.0)

3868 1447 645 811

(57.1) (21.4) (9.53) (12.0)

6305 4208 427 72 581

(93.1) (62.2) (6.31) (1.06) (8.58)

6303 4185 463 95 536

(93.1) (61.8) (6.84) (1.40) (7.92)

0.19 0.78

0.93

0.99

Student t-test. CCI score = Charlson comorbidity index score.

0.95 0.68 0.21 0.07 0.16

C.-S. Lin et al. / International Journal of Cardiology 184 (2015) 9–13

incidence of cancer was lower for the carvedilol cohort than for the noncarvedilol cohort (log-rank test: p b .001) (Fig. 1). The overall sex- and age-specific incidence rates and HR of these two cohorts are shown in Table 2. The overall incidence density of cancer was significantly lower in the carvedilol cohort than in the noncarvedilol cohort (9.77 vs 11.9 per 1000 person-y). The patients in the carvedilol cohort had a 26% lower cancer risk compared with patients in the noncarvedilol cohort (95% CI = 0.63–0.87). The incidence density of cancer was higher in men than in women for both cohorts. The sexspecific carvedilol to noncarvedilol relative risk was lower for both women (HR = 0.73; 95% CI = 0.56–0.94) and men (HR = 0.75; 95% CI = 0.61–0.92). The incidence of cancer increased with age in both cohorts, and the age-specific carvedilol to noncarvedilol relative risk was lower for all age groups. Table 3 shows the analyses of specific cancer types in the carvedilol and noncarvedilol cohorts. We observed that subjects using carvedilol showed a decreased risk of upper gastrointestinal (GI) tract cancer (HR = 0.30, 99.5% CI = 0.10–0.87). The risk of lung cancer was also significantly lower for patients in the carvedilol cohort than in the noncarvedilol cohort (HR = 0.59, 95% CI = 0.37–0.94). In addition, the duration of carvedilol use was associated with the risk of upper GI tract cancer, and lung cancer. Table 4 shows the risk of upper GI tract cancer and lung cancer stratified according to the duration of carvedilol use. The risk of upper GI tract cancer decreased when the patients used carvedilol for longer than 1095 days. 4. Discussion In this nationwide population-based retrospective cohort study, we observed a significant 26% reduction of cancer risk in patients receiving long-term carvedilol treatment compared with the noncarvedilol cohort, irrespective of age, sex, and baseline comorbidities such as hypertension, coronary artery disease, and AF. When we focused on certain cancer types, patients treated with carvedilol had a significant reduction of upper GI tract (HR = 0.30; 99.55% CI = 0.10–0.87) and lung (HR = 0.59; 95% CI = 0.37–0.94) cancer risks, compared with patients in the noncarvedilol cohort. These results indicated the beneficial effects of carvedilol in cancer prevention, particularly upper GI tract and lung cancers. The NHIRD used in the present investigation is an effective database to provide population-based studies with age- and sex-matched groups.

Fig. 1. Cumulative incidence of cancer compared between carvedilol cohort and noncarvedilol cohort.

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Table 2 Comparison of incidence and hazard ratio of cancer stratified by sex and age according to medication status. Carvedilol No

All Gender Women Men Age b64 65+

Yes #

Rate#

HR#(95% CI)

Event

PY

11.9

342

35,020

9.77

0.74 (0.63, 0.87)⁎⁎⁎

14,944 18,436

10.2 13.3

119 223

15,644 19,376

7.61 11.5

0.73 (0.56, 0.94)⁎ 0.75 (0.61, 0.92)⁎⁎

18,771 14,609

8.52 16.3

121 221

19,303 15,717

6.27 14.1

0.74 (0.56, 0.98)⁎ 0.75 (0.60, 0.94)⁎

Event

PY

Rate

398

33,380

152 246 160 238

PY, person-years; Rate#, incidence rate, per 1000 person-years; HR#, relative hazard ratio. ⁎ p b 0.05. ⁎⁎ p b 0.01. ⁎⁎⁎ p b 0.001.

Because participation in the NHI program is mandatory and all Taiwanese residents can access medical care with low copayments, the loss to follow-up is low. Moreover, prescription of carvedilol is based on complete clinical electrocardiographic and echocardiographic assessments. Pathologic proof of malignancy is necessary to apply for a cancer catastrophic illness certificate to obtain exemption from related medical costs such as hospital expenses; therefore, data regarding the use of carvedilol and cancer diagnosis were reliable in the current study. As we mentioned above, carvedilol as well as other types of βblockers are being used to treat chronic stable disease, such as CAD, hypertension, and heart failure [7,8]. This suggests that long-term use of carvedilol is not a big concern regarding its safety issue. Moreover, although the most common adverse reactions of carvedilol were edema, dizziness, bradycardia, and hypotension, most patients tolerate it well even in chronic use. Similar to other types of β-blockers, only 5% of patients who taking carvedilol finally discontinued it [13]. Such evidence elucidates the safety and efficacy of carvedilol in its longterm use. Regarding the underlying mechanisms of how carvedilol reduces cancer risk, previous studies have suggested that carvedilol exhibits anticancer activities by arresting cells at the G0/G1 phase, inducing apoptosis and causing severe mitochondria damage in glioma cells [9]. In addition to antiproliferative and antiangiogenic effects, carvedilol reverses multidrug resistance to anticancer drugs through Pglycoprotein inhibition, which can enhance response to chemotherapy [2,9,14]. Moreover, compared with other β-blockers, carvedilol exerts potent and multifaceted therapeutic effects including antioxidant and anti-inflammatory properties. Carvedilol, but not propranolol, inhibits intracellular reactive oxygen species production, tumornecrosis-factor-alpha-stimulated NF-κB and activator protein-1 transcription factors activation, and inflammatory cytokine expression in human mononuclear cells [15–18]. Additional in vivo investigations have suggested that carvedilol reduces matrix metalloproteinase (MMP)-2 and MMP-9 expression, likely through modulation of redoxrelated pathways [19]. This evidence supports and elucidates the anticancer effects of carvedilol. Observational studies have revealed controversial clinical results of β-blocker use in cancer patients. Inhibition of the β2-adrenergic pathway has been shown to reduce breast cancer progression and mortality [20]. Furthermore, treatment with β-blockers provides clinical benefits to patients with breast, melanoma, and ovarian cancers, or non-small cell lung cancer (NSCLC) [21–24]. Unlike the beneficial roles of β-blockers in cancer patients, a large cohort study suggested that the use of β-blockers is not associated with a decreased risk of prostate cancer and all-cause mortality [25]. McCourt et al. suggested that the use of β-blockers after the diagnosis of malignant melanoma is not associated with reduced risk of death from melanoma in a population-based study conducted in the United Kingdom [26]. Given these potentially

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Table 3 Comparison of incidence and hazard ratio of sub-division cancer and treatment according to medication status. Carvedilol No

Yes

Cancer (ICD-9-CM)

Event

Rate#

Event

Rate#

HR#(95% CI)

HR#(99.5% CI)

Hematologic malignancy (200–208) Head and neck (140–149, 161) Upper GI tract cancer (150–151) Colon (153–154) Hepatoma (155) Lung (162) Female breast (174) Uterus (180–184) Prostate (185) Urinary system cancer (188–189) Others

13 30 34 66 56 55 23 16 30 27 38

0.39 0.90 1.02 1.98 1.68 1.65 1.54 1.07 1.63 0.81 1.14

16 22 16 70 45 44 24 12 27 29 29

0.46 0.63 0.46 2.00 1.28 1.26 1.53 0.77 1.39 0.83 0.83

0.67 (0.27, 1.63) 0.68 (0.38, 1.22) 0.30 (0.14, 0.63)⁎ 0.96 (0.66, 1.41) 0.74 (0.48, 1.13) 0.59 (0.37, 0.94)⁎

0.67 (0.19, 2.40) 0.68 (0.30, 1.56) 0.30 (0.10, 0.87)⁎⁎ 0.96 (0.56, 1.65) 0.74 (0.40, 1.36) 0.59 (0.31, 1.14) 0.96 (0.41, 2.25) 0.67 (0.21, 2.10) 0.74 (0.32, 1.70) 1.05 (0.45, 2.42) 0.74 (0.34, 1.61)

0.96 (0.53, 1.74) 0.67 (0.30, 1.48) 0.74 (0.42, 1.32) 1.05 (0.58, 1.88) 0.74 (0.43, 1.27)

PY, person-years; Rate#, incidence rate, per 1000 person-years; HR#, relative hazard ratio. ⁎ p b 0.05. ⁎⁎ p b 0.005.

disputable findings, the role of β-blockers in cancer prevention remains unclear. These controversial results might be due to various cancer types and antitumor activities of different β-blockers. We demonstrated that the long-term use of carvedilol is associated with reduced upper GI tract cancer risk (Table 3). Although the relative HR on upper GI tract cancer is higher in patients who took carvedilol less than 1095 days than those who did not take carvedilol, this trend did not reach statistical significance. Interestingly, there are significantly beneficial effects of carvedilol on upper GI tract cancer risk in patients treated with carvedilol for longer than 1,095 days, indicating the dosedependent effects of carvedilol on upper GI tract cancer (Table 4). Previous report suggested that the β-adrenergic signaling pathway mediates chloroform extract of cigarette smoke induced proliferation of human esophageal squamous cell carcinoma cells [27]. Additionally, other βblocker, such as propranolol has been reported to induce apoptosis and repress stomach cancer cell growth through the inhibition of the downstream NF-κB, VEGF, MMPs, and cyclooxygenase-2 pathways [28]. These results provide strong evidence of the therapeutic potential of carvedilol on upper GI tract cancers. In addition to upper GI tract cancer, the risk of lung cancer was lower in patients treated with carvedilol (Table 3). Although the effects of carvedilol on lung cancer have not been reported, previous in vitro studies have suggested that exposure to nicotine through tobacco smoke or nicotine supplements facilitates the growth and progression of NSCLC, which might be suppressed by propranolol [29]. Furthermore, Wang et al. indicated that the use of β-blockers improved survival outcome in NSCLC patients receiving radiation therapy [24]. The results indicate Table 4 Incidence and adjusted hazard ratio of sub-division cancer stratified by duration of carvedilol use. Carvedilol exposed& N

Event Rate† HR#(95% CI)

HR#(99.5% CI)

Upper GI tract cancer No use 6771 34

1.02

1.00

Duration on carvedilol ≤1095 days 2060 6 N1095 days 4711 10

0.77 0.37

1.25 (0.34, 4.65) 1.25 (0.19, 8.22) 0.15 (0.05, 0.44)⁎ 0.15 (0.03, 0.70)⁎⁎

Lung cancer No use

6771 55

1.65

1.00

1.00

Duration on carvedilol ≤1095 days 2060 14 N1095 days 4711 30

1.79 1.10

0.56 (0.26, 1.20) 0.61 (0.35, 1.09)

0.56 (0.18, 1.68) 0.61 (0.27, 1.39)

1.00

PY, person-years; Rate†, incidence rate, per 1000 person-years; HR#, relative hazard ratio. The duration on carvedilol use is partitioned in to 2 segments by first quartile. ⁎ p b 0.05. ⁎⁎ p b 0.005.

that β-blockers may reduce the risk of NSCLC among smokers and could be used to improve the clinical outcome of standard cancer therapy. However, since reports related to carvedilol and lung cancer are scant, and dose effect of carvedilol use on lung cancer could not be observed in the current study (Table 4), the effects of carvedilol on lung cancer must be confirmed. The present study did not reveal a significant difference in reduction of colon cancer risk in patients who received carvedilol treatment compared with those who did not, as shown in Table 3. Jansen et al. demonstrated that β-blocker use is not associated with a decreased risk of colorectal cancer [30], which is in agreement with our findings. In the Jansen et al. case–control study, 1762 colorectal cancer patients and 1708 control patients from Germany were included, who were followed up for 5 years. Despite analysis of subclasses of β-blockers, treatment with cardioselective or nonselective β-blockers, such as carvedilol, did not reduce the risk of colorectal cancer. These results suggest that carvedilol might not be helpful in reducing colorectal cancer risk. Although a strength of this study was the use of a nationwide population-based cohort longitudinal analysis of the risk of cancer in Asian patients treated with carvedilol, several limitations should be considered before interpreting the findings. The NHIRD does not provide detailed information on the lifestyle or health-related factors of patients, such as smoking, alcohol consumption, body mass index, socioeconomic status, and family history of malignancy, which can increase the risk of cancer and were potential confounding factors in this study. Moreover, evidence from a cohort study is generally considered to be of lower methodological quality than that from randomized trials. An additional limitation is that we were unable to evaluate the regular use of carvedilol. Only the information regarding the use of carvedilol or not is provided by the NHIRD. Therefore, the dose–response relationship is demonstrated by cumulative duration of use, as indicated in Table 4. Although patients treated with carvedilol for b 2 years were excluded from our analysis, lifetime exposure could not be estimated, and the cumulative duration of use may have been underestimated. Finally, despite the scrupulous study design to control the confounding factors, a key limitation of this study was its potential bias resulting from possible unmeasured or unknown confounders. However, as our previously published work regarding the effects of benzodiazepine on cancer risk [31], the current study provides valuable information regarding the effects of carvedilol on the reduction of cancer risk even with these limitations. In conclusion, we demonstrated for the first time that carvedilol is associated with reduced certain types of cancer and overall cancer risk in a large population-based cohort study. This study revealed the therapeutic potential of carvedilol in upper GI tract and lung cancers prevention. Additional prospective randomized studies as well as in vivo and

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in vitro studies are necessary to verify the effects of carvedilol on cancer risk and elucidate its possible underlying mechanisms. Author contributions All authors have contributed substantially to, and are in agreement with the content of, the manuscript: Conception/Design: Chin-Sheng Lin, Chia-Hung Kao; Provision of study materials: Chia-Hung Kao; Collection and/or assembly of data: Chin-Sheng Lin, Cheng-Li Lin, Chia-Hung Kao; Data analysis and interpretation: All authors; Manuscript preparation: All authors; Final approval of manuscript: All authors. Conflict of interest All authors report no conflicts of interest. Acknowledgments C.S. Lin was supported by grants from the Tri-Service General Hospital (TSGH-C104-026) and the Taiwan Ministry of Science and Technology (MOST 103-2628-B-016-002-MY3); the Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002), Health and welfare surcharge of tobacco products, the China Medical University Hospital Cancer Research Center of Excellence (MOHW104-TD-B-111-03, Taiwan). The funders had no role in study design, data collection or analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. References [1] S.W. Cole, A.K. Sood, Molecular pathways: beta-adrenergic signaling in cancer, Clin. Cancer Res. 18 (2012) 1201–1206. [2] E. Pasquier, J. Street, C. Pouchy, M. Carre, A.J. Gifford, J. Murray, et al., Beta-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma, Br. J. Cancer 108 (2013) 2485–2494. [3] P.H. Thaker, L.Y. Han, A.A. Kamat, J.M. Arevalo, R. Takahashi, C. Lu, et al., Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma, Nat. Med. 12 (2006) 939–944. [4] E.K. Sloan, S.J. Priceman, B.F. Cox, S. Yu, M.A. Pimentel, V. Tangkanangnukul, et al., The sympathetic nervous system induces a metastatic switch in primary breast cancer, Cancer Res. 70 (2010) 7042–7052. [5] H. Chim, B.S. Armijo, E. Miller, C. Gliniak, M.A. Serret, A.K. Gosain, Propranolol induces regression of hemangioma cells through HIF-1alpha-mediated inhibition of VEGF-A, Ann. Surg. 256 (2012) 146–156. [6] T. Shan, Q. Ma, D. Zhang, K. Guo, H. Liu, F. Wang, et al., Beta2-adrenoceptor blocker synergizes with gemcitabine to inhibit the proliferation of pancreatic cancer cells via apoptosis induction, Eur. J. Pharmacol. 665 (2011) 1–7. [7] W.H. Frishman, Carvedilol, N. Engl. J. Med. 339 (1998) 1759–1765. [8] T.L. Yue, P.J. McKenna, P.G. Lysko, J.L. Gu, K.A. Lysko, R.R. Ruffolo Jr., et al., SB 211475, a metabolite of carvedilol, a novel antihypertensive agent, is a potent antioxidant, Eur. J. Pharmacol. 251 (1994) 237–243. [9] M. Erguven, N. Yazihan, E. Aktas, A. Sabanci, C.J. Li, G. Oktem, et al., Carvedilol in glioma treatment alone and with imatinib in vitro, Int. J. Oncol. 36 (2010) 857–866.

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