Calcium channel blockers are among the most commonly used agents in the treatment of cardiovascular diseases. There are several known side-effects associated with their long-term use, whereas other potential adverse effects are yet to be proven. This study aims to evaluate the association between calcium channel blockers exposure and the incidence of second primary malignancy. We established a cohort of 1401 patients with colorectal cancer diagnosed in our institution between January 2003 and December 2016. Patients were followed-up until December 2020. The tumor characteristics and basic clinical data including medication information were obtained from the hospital information system database. Second malignancy was detected in 301 patients (21.5%), and occurred in 27.8% of patients who used calcium channel blockers compared to only 19.9% among non-users. Their use was associated with an increased incidence of bladder cancer in particular. Subanalysis of patients with second malignancy displayed a higher proportion of right-sided colon cancer compared to rectal carcinoma in non-users. Survival analysis revealed significantly better outcomes in early-stage colorectal cancer patients without a history of calcium channel blockers treatment or second primary malignancy.

Clinical Trial Unit Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Breast Skin and Oncoplastic Surgery Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Comprehensive Cancer Care Faculty of Medicine Masaryk University Brno Czech Republic

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute Brno Czech Republic

Department of General Surgical Oncology Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Gynecologic Oncology Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Pharmacology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pharmacy Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Pharmacy University Hospital Brno Brno Czech Republic

Department of Radiation Oncology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Radiation Oncology Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Surgical Oncology Faculty of Medicine Masaryk University Brno Czech Republic

Institute of Biostatistics and Analyses Faculty of Medicine Masaryk University Brno Czech Republic

Institute of Health Information and Statistics of the Czech Republic Prague Czech Republic

Masaryk Memorial Cancer Institute Žlutý Kopec 7 656 53 Brno Czech Republic

Research Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute Brno Czech Republic

Zobrazit více v PubMed

Institute of Health Information and Statistics of the Czech Republic. Cancer Incidence in the Czech Republic. Czech National Cancer Registry. http://www.uzis.cz/registry-nzis/nor. Accessed 9 February 2022.

Ferlay, J. et al. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. https://gco.iarc.fr/today. Accessed 9 February 2022.

Soerjomataram I, Coebergh JW. Epidemiology of multiple primary cancers. In: Verma M, editor. Cancer Epidemiology. Humana Press; 2009. pp. 85–105. PubMed

Bong AHL, Monteith GR. Calcium signaling and the therapeutic targeting of cancer cells. Biochim. Biophys. Acta BBA—Mol. Cell Res. 2018;1865:1786–1794. doi: 10.1016/j.bbamcr.2018.05.015. PubMed DOI

Honn KV, Onoda JM, Diglio CA, Sloane BF. Calcium channel blockers: Potential antimetastatic agents. Exp. Biol. Med. 1983;174:16–19. doi: 10.3181/00379727-174-1-RC2. PubMed DOI

Pahor M, et al. Calcium-channel blockade and incidence of cancer in aged populations. Lancet Lond. Engl. 1996;348:493–497. doi: 10.1016/S0140-6736(96)04277-8. PubMed DOI

Fitzpatrick AL, Daling JR, Furberg CD, Kronmal RA, Weissfeld JL. Use of calcium channel blockers and breast carcinoma risk in postmenopausal women. Cancer. 1997;80:1438–1447. doi: 10.1002/(SICI)1097-0142(19971015)80:8<1438::AID-CNCR11>3.0.CO;2-6. PubMed DOI

Stewart TA, Yapa KTDS, Monteith GR. Altered calcium signaling in cancer cells. Biochim. Biophys. Acta BBA—Biomembr. 2015;1848:2502–2511. doi: 10.1016/j.bbamem.2014.08.016. PubMed DOI

Trump BF, Berezesky IK. Calcium-mediated cell injury and cell death. FASEB J. 1995;9:219–228. doi: 10.1096/fasebj.9.2.7781924. PubMed DOI

Déliot N, Constantin B. Plasma membrane calcium channels in cancer: Alterations and consequences for cell proliferation and migration. Biochim. Biophys. Acta BBA—Biomembr. 2015;1848:2512–2522. doi: 10.1016/j.bbamem.2015.06.009. PubMed DOI

Monteith GR, McAndrew D, Faddy HM, Roberts-Thomson SJ. Calcium and cancer: Targeting Ca2+ transport. Nat. Rev. Cancer. 2007;7:519–530. doi: 10.1038/nrc2171. PubMed DOI

Roderick HL, Cook SJ. Ca2+ signalling checkpoints in cancer: Remodelling Ca2+ for cancer cell proliferation and survival. Nat. Rev. Cancer. 2008;8:361–375. doi: 10.1038/nrc2374. PubMed DOI

Matsumori A, Nishio R, Nose Y. Calcium channel blockers differentially modulate cytokine production by peripheral blood mononuclear cells. Circ. J. 2010;74:567–571. doi: 10.1253/circj.CJ-09-0467. PubMed DOI

Roberts-Thomson SJ, Chalmers SB, Monteith GR. The Calcium-signaling toolkit in cancer: Remodeling and targeting. Cold Spring Harb. Perspect. Biol. 2019;11:a035204. doi: 10.1101/cshperspect.a035204. PubMed DOI PMC

Olsen JH, et al. Cancer risk in users of calcium channel blockers. Hypertension. 1997;29:1091–1094. doi: 10.1161/01.HYP.29.5.1091. PubMed DOI

Rosenberg L, et al. Calcium channel blockers and the risk of cancer. JAMA. 1998;279:1000–1004. doi: 10.1001/jama.279.13.1000. PubMed DOI

Jick H, et al. Calcium-channel blockers and risk of cancer. Lancet. 1997;349:525–528. doi: 10.1016/S0140-6736(97)80084-0. PubMed DOI

Hole DJ, et al. Cancer risk of hypertensive patients taking calcium antagonists. J. Hypertens. 1998;16:119–124. doi: 10.1097/00004872-199816010-00017. PubMed DOI

Vogt, A. et al. Multiple primary tumours: Challenges and approaches, a review. ESMO Open2(2), (2017). PubMed PMC

Johnson, C.H. et al. Multiple primary and histology coding rules. Natl. Cancer Inst. Surveill. Epidemiol. End Results Program Bethesda MD (2007).

Rotshild V, et al. The risk for lung cancer incidence with calcium channel blockers: A systematic review and meta-analysis of observational studies. Drug Saf. 2018;41:555–564. doi: 10.1007/s40264-018-0644-4. PubMed DOI

Li CI, et al. Use of antihypertensive medications and breast cancer risk among women aged 55 to 74 years. JAMA Intern. Med. 2013;173:1629–1637. doi: 10.1001/jamainternmed.2013.9071. PubMed DOI PMC

Xie, Y. et al. Association between antihypertensive medication use and breast cancer: A systematic review and meta-analysis. Front. Pharmacol.12, (2021). PubMed PMC

Yang H, et al. Association between the overall risk of prostate cancer and use of calcium channel blockers: A systematic review and meta-analysis. Clin. Ther. 2020;42:1715–1727.e2. doi: 10.1016/j.clinthera.2020.06.021. PubMed DOI

Guercio V, et al. Bladder cancer risk in users of selected drugs for cardiovascular disease prevention. Eur. J. Cancer Prev. 2019;28(2):76–80. doi: 10.1097/CEJ.0000000000000419. PubMed DOI

Xie Y, et al. Antihypertensive medications are associated with the risk of kidney and bladder cancer: A systematic review and meta-analysis. Aging. 2020;12:1545–1562. doi: 10.18632/aging.102699. PubMed DOI PMC

Matsui S, et al. Long-term antihypertensive drug use and risk of cancer: The Japan Public Health Center-based prospective study. Cancer Sci. 2021;112:1997–1997. doi: 10.1111/cas.14870. PubMed DOI PMC

Cho I-J, et al. Antihypertensive drugs and the risk of cancer: A nationwide cohort study. J. Clin. Med. 2021;10:771. doi: 10.3390/jcm10040771. PubMed DOI PMC

Copland E, et al. Antihypertensive treatment and risk of cancer: An individual participant data meta-analysis. Lancet Oncol. 2021;22:558–570. doi: 10.1016/S1470-2045(21)00033-4. PubMed DOI PMC

Bergman GJ, Khan S, Danielsson B, Borg N. Breast cancer risk and use of calcium channel blockers using swedish population registries. JAMA Intern. Med. 2014;174:1700–1701. doi: 10.1001/jamainternmed.2014.3867. PubMed DOI

Azoulay L, Soldera S, Yin H, Bouganim N. Use of calcium channel blockers and risk of breast cancer. Epidemiology. 2016;27:594–601. doi: 10.1097/EDE.0000000000000483. PubMed DOI

Raebel MA, et al. Risk of breast cancer with long-term use of calcium channel blockers or angiotensin-converting enzyme inhibitors among older women. Am. J. Epidemiol. 2017;185:264–273. doi: 10.1093/aje/kww217. PubMed DOI

Chen Q, et al. Association between calcium channel blockers and breast cancer: A meta-analysis of observational studies. Pharmacoepidemiol. Drug Saf. 2014;23:711–718. doi: 10.1002/pds.3645. PubMed DOI

Devore EE, et al. Antihypertensive medication use and incident breast cancer in women. Breast Cancer Res. Treat. 2015;150:219. doi: 10.1007/s10549-015-3311-9. PubMed DOI PMC

Poch MA, et al. The association between calcium channel blocker use and prostate cancer outcome. Prostate. 2013;73:865. doi: 10.1002/pros.22632. PubMed DOI PMC

Grimaldi-Bensouda L, et al. Calcium channel blockers and cancer: A risk analysis using the UK Clinical Practice Research Datalink (CPRD) BMJ Open. 2016;6:1–7. doi: 10.1136/bmjopen-2015-009147. PubMed DOI PMC

Mason RP. Calcium channel blockers, apoptosis and cancer: Is there a biologic relationship? J. Am. Coll. Cardiol. 1999;34:1857–1866. doi: 10.1016/S0735-1097(99)00447-7. PubMed DOI

Balkrishnan R, et al. Associations between initiating antihypertensive regimens on stage I-III colorectal cancer outcomes: A Medicare SEER cohort analysis. Cancer Med. 2021;10:5347–5357. doi: 10.1002/cam4.4088. PubMed DOI PMC

Peng F, et al. Impact of long-term antihypertensive and antidiabetic medications on the prognosis of post-surgical colorectal cancer: The Fujian prospective investigation of cancer (FIESTA) study. Aging. 2018;10:1166. doi: 10.18632/aging.101459. PubMed DOI PMC