Does Beta-blocker Therapy Improve the Survival of Patients with Metastatic Non-small Cell Lung Cancer?

  • Aydiner, Adnan (Medical Oncology Department, Institute of Oncology, Istanbul University) ;
  • Ciftci, Rumeysa (Medical Oncology Department, Institute of Oncology, Istanbul University) ;
  • Karabulut, Senem (Medical Oncology Department, Institute of Oncology, Istanbul University) ;
  • Kilic, Leyla (Medical Oncology Department, Institute of Oncology, Istanbul University)
  • Published : 2013.10.30


Aim: To determine whether beta-blockers (BBs) improve the overall survival (OS) of patients with metastatic non-small cell lung cancer (NSCLC). Materials and Methods: The medical charts of 107 patients with metastatic NSCLC were retrospectively assessed. Thirty-five patients (BB group) using BBs during chemotherapy (CT) were compared with 72 controls [control=(C) group] who did not use BBs following the diagnosis of NSCLC. The histological tumor subtype, performance status (ECOG), age, gender, smoking status, comorbidities, other medications and chemotherapeutics that were received in any line of treatment were recorded. We compared the overall survival (OS) of the patients in the BB and C groups. Results: The mean age of the patients was 61 years (range 42-81 years) and all patients were administered CT. The BB group was more likely to have HT and IHD and was more likely to use RAS blockers (p<0.01 for all) compared with the C group, as expected. The mean follow-up time was 17.8 months (range 1-102 months) for the entire group. The most commonly prescribed BB agent was metoprolol (80% of cases). At the time of the analysis, 74 (69%) of all patients had died. In the univariate analysis the median overall survival (OS) was 19.25 (${\pm}2.87$) months (95%CI: 13.62-24.88) in the BB group and 13.20 (${\pm}2.37$) months (95%CI: 8.55-17.85) in the C group (p=0.017). However, the benefit of BBs on survival disappeared in the multivariate analysis. Conclusions: The use of BBs during CT may be associated with an improved OS for patients with metastatic NSCLC.


Beta;blockers;non-small cell lung cancer;survival


  1. Al-Wadei HA, Ullah MF, Al-Wadei MH (2012). Intercepting neoplastic progression in lung malignancies via the beta adrenergic (${\beta}$-AR) pathway: implications for anti-cancer drug targets. Pharmacol Res, 66, 33-40.
  2. Al-Wadei HA, Schuller HM (2009). Nicotinic receptor-associated modulation of stimulatory and inhibitory neurotransmitters in NNK-induced adenocarcinoma of the lungs and pancreas. J Pathol, 218, 437-45.
  3. Al-Wadei HA, Plummer HK, Schuller HM (2009). Nicotine stimulates pancreatic cancer xenografts by systemic increase in stress neurotransmitters and suppression of the inhibitory neurotransmitter gamma-aminobutyric acid. Carcinogenesis, 30, 506-11.
  4. Al-Wadei HA, Al-Wadei MH, Ullah MF, et al (2012). Gamma-amino butyric acid inhibits the nicotine-imposed stimulatory challenge in xenograft models of non-small cell lung carcinoma. Curr Cancer Drug Targets, 12, 97-106.
  5. Al-Wadei HA, Al-Wadei MH, Schuller HM (2012). Cooperative regulation of non-small cell lung carcinoma by nicotinic and beta-adrenergic receptors: a novel target for intervention. PLoS One, 7, 29915.
  6. Arredondo J, Chernyavsky AI, Grando SA (2006). Nicotinic receptors mediate tumorigenic action of tobacco-derived nitrosamines on immortalized oral epithelial cells. Cancer Biol Ther, 5, 511-7.
  7. Ben-Eliyahu S, Shakhar G, Page GG, et al (2000). Suppression of NK cell activity and of resistance to metastasis by stress: a role for adrenal catecholamines andbeta-adrenoceptors. Neuroimmunomodulation, 8, 154-64.
  8. Drell TL, Joseph J, Lang K, et al (2003). Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. Breast Cancer Res Treat, 80, 63-70.
  9. Carlisle DL, Liu X, Hopkins TM, et al (2007). Nicotine activates cell-signaling pathways through muscle-type and neuronal nicotinic acetylcholine receptors in non-small cell lung cancer cells. Pulm Pharmacol Ther, 20, 629-41.
  10. Catassi A, Servent D, Paleari L, et al (2008). Multiple roles of nicotine on cell proliferation and inhibition of apoptosis: implications on lung carcinogenesis. Mutat Res, 659, 221-31.
  11. Cole SW, Sood AK (2012). Molecular pathways: beta-adrenergic signaling in cancer. Clin Cancer Res, 18, 1201-6.
  12. Jemal A, Siegel R, Ward E, et al (2007). Cancer statistics, 2007. CA Cancer J Clin, 57, 43-66.
  13. Kondratenko TIa, Kuzina NV, Severin ES, et al (1991). Beta-Adrenergic and muscarinic acetylcholine receptors in human lung parenchyma in malignant neoplasms. Vopr Med Khim, 37, 20-1.
  14. Kondratenko TY, Zacharova IV, Kuzina NV, et al (1993). Alterations in human lung adrenergic receptors in cancer. Biochem Mol Biol Int, 29, 123-30.
  15. Laag E, Majidi M, Cekanova M, et al (2006). NNK activates ERK1/2 and CREB/ATF-1 via beta-1-AR and EGFR signaling in human lung adenocarcinoma and small airway epithelial cells. Int J Cancer, 119, 1547-52.
  16. Masur K, Niggemann B, Zanker KS, et al (2001). Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers. Cancer Res, 61, 2866-9.
  17. Salpeter SS, Ormiston T, Salpeter E, et al (2002). Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev, 2, 3566.
  18. Morin D, Zini R, Lange F, et al (1987). Alterations of beta-adrenergic, muscarinic cholinergic receptors and imipramine binding sites in human lungtumors. Int J Clin Pharmacol Ther Toxicol, 25, 605-8.
  19. Palm D, Lang K, Niggemann B, et al (2006). The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by beta-blockers. Int J Cancer, 118, 2744-9.
  20. Powe DG, Voss MJ, Zanker KS, et al (2010). Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improvescancer specific survival. Oncotarget, 1, 628-38.
  21. Schuller HM, Orloff M (1998). Tobacco-specific carcinogenic nitrosamines. Ligands for nicotinic acetylcholine receptors in human lung cancer cells. Biochem Pharmacol, 55, 1377-83.
  22. Schuller HM, Tithof PK, Williams M, et al (1999). The tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a beta-adrenergic agonist and stimulates DNA synthesis in lung adenocarcinoma via beta-adrenergic receptor-mediated release of arachidonic acid. Cancer Res, 59, 4510-5.
  23. Schuller HM, Porter B, Riechert A (2000). Beta-adrenergic modulation of NNK-induced lung carcinogenesis in hamsters. J Cancer Res Clin Oncol, 126, 624-30.
  24. Schuller HM, Cekanova M (2005). NNK-induced hamster lung adenocarcinomas over-express beta2-adrenergic and EGFR signaling pathways. Lung Cancer, 49, 35-45.
  25. Schuller HM (2008). Neurotransmission and cancer: implications for prevention and therapy. Anticancer Drugs, 19, 655-71.
  26. Thaker PH, Han LY, Kamat AA, et al (2006). Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med, 12, 939-44.
  27. Schuller HM (2009). Is cancer triggered by altered signalling of nicotinic acetylcholine receptors? Nat Rev Cancer, 9, 195-205.
  28. Shah SM, Carey IM, Owen CG, et al (2011). Does ${\beta}$-adrenoceptor blocker therapy improve cancer survival? Findings from a population-based retrospective cohort study. Br J Clin Pharmacol, 72, 157-61.
  29. Sood AK, Bhatty R, Kamat AA, et al (2006). Stress hormone-mediated invasion of ovarian cancer cells. Clin Cancer Res, 12, 369-75.
  30. Wang HM, Liao ZX, Komaki R, et al (2013). 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, 24, 1312-9.
  31. West KA, Linnoila IR, Belinsky SA, et al (2004). Tobacco carcinogen-induced cellular transformation increases activation of the phosphatidylinositol 3'-kinase/Akt pathway in vitro and in vivo. Cancer Res, 64, 446-51.
  32. Wong HP, Yu L, Lam EK, et al (2007). Nicotine promotes colon tumor growth and angiogenesis through beta-adrenergic activation. Toxicol Sci, 97, 279-87.
  33. Wong HP, Yu L, Lam EK, et al (2007). Nicotine promotes cell proliferation via alpha7-nicotinic acetylcholine receptor and catecholamine-synthesizing enzymes-mediated pathway in human colon adenocarcinoma HT-29 cells. Toxicol Appl Pharmacol, 221, 261-7.
  34. Wong DL, Tai TC, Wong-Faull DC, et al (2011). Epinephrine: a short- and long-term regulator of stress and development of illness: a potential new role for epinephrine in stress. Cell Mol Neurobiol, 32, 737-48.

Cited by

  1. Radiosensitization Effect of Overexpression of Adenovirus-mediated SIRT6 on A549 Non-small Cell Lung Cancer Cells vol.15, pp.17, 2014,
  2. Expression of ERCC1, RRM1 and LRP in Non-small Cell Lung Cancers and their Influence on Chemotherapeutic Efficacy of Gemcitabine Concomitant with Nedaplatin vol.15, pp.17, 2014,
  3. Experimental Study on Inhibition Effects of the XAF1 Gene against Lung Cancer Cell Proliferation vol.15, pp.18, 2014,
  4. Are Beta Blockers New Potential Anticancer Agents? vol.15, pp.22, 2014,
  5. Sympathetic nervous system regulation of the tumour microenvironment vol.15, pp.9, 2015,
  6. β-Blocker use and mortality in cancer patients vol.25, pp.5, 2016,
  7. Propranolol enhances bone healing and implant osseointegration in rats tibiae vol.43, pp.12, 2016,
  8. Pre- and post-diagnostic β-blocker use and lung cancer survival: A population-based cohort study vol.7, pp.1, 2017,
  9. Infantile Hemangiomas, Retinopathy of Prematurity and Cancer: A Common Pathogenetic Role of the β-Adrenergic System vol.35, pp.3, 2014,
  10. Repurposing existing medications as cancer therapy: design and feasibility of a randomized pilot investigating propranolol administration in patients receiving hematopoietic cell transplantation vol.18, pp.1, 2018,