Hydrochlorothiazide and the risk of non-melanoma skin cancer: a critical review
https://doi.org/10.18705/1607-419X-2019-25-4-376-388
Abstract
Several recent large studies, most of which were performed in Denmark, have revealed a link between hydrochlorothiazide use and the risk of non-melanoma skin cancer. Photosensitizing properties of hydrochlorothiazide, inherent in many antihypertensive drugs, are considered a key pathophysiological mechanism underlying this association. The results of these studies prompted an update to the recommendations of the European Medical Agency for the safety of hydrochlorothiazide. However, to date there have been no convincing evidence of causality of this association. The accumulation of data on usage of hydrochlorothiazide, the most widely used diuretic worldwide, made the discussion of this association possible despite the low prevalence of skin cancer. At the same time, the retrospective design of these studies should be considered, as well as limited sample and lack of adjustment for important confounders. Therefore, the results obtained in these studies must be interpreted with extreme caution to prevent the decrease in hypertension control due to reduced compliance with treatment, unjustified withdrawal or replacement of hydrochlorothiazide, including its fixed combinations, with other thiazide or thiazide-like diuretics, which also have photosensitizing action.
About the Authors
Zh. D. KobalavaRussian Federation
Zhanna D. Kobalava, MD, PhD, DSc, Professor, Head, Department of Internal Medicine with Course of Cardiology and Functional Diagnostics named after V. S. Moiseev, RUDN University
Moscow
E. V. Kokhan
Russian Federation
Elizaveta V. Kokhan, MD, Resident, Department of Internal Medicine with Course of Cardiology and Functional Diagnostics named after V. S. Moiseev, RUDN University
61 Vavilov street, Moscow, 117292
G. K. Kiyakbaev
Russian Federation
Gayrat K. Kiyakbaev, MD, PhD, DSc, Professor, Department of Internal Medicine with Course of Cardiology and Functional Diagnostics named after V. S. Moiseev, RUDN University
Moscow
References
1. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M,Burnier M et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021–3104. doi:10.1093/eurheartj/ehy339
2. Mouhayar E, Salahudeen A. Hypertension in cancer patients. Texas Hear Inst J. 2011;38(3):263–265.
3. Małyszko J, Małyszko M, Kozlowski L, Kozlowska K, Małyszko J. Hypertension in malignancy-an underappreciated problem. Oncotarget. 2018;9(29):20855–20871. doi:10.18632/oncotarget.25024
4. Rotshild V, Azoulay L, Feldhamer I, Perlman A, Glazer M, Muszkat M et al. Calcium channel blockers and the risk for lung cancer: a population-based nested case-control study. Ann Pharmacother. 2019;53(5):445–452. doi:10.1177/1060028018814684
5. Chen L, Chubak J, Boudreau DM, Barlow WE, Weiss NS, Li CI.Use of antihypertensive medications and risk of adverse breast cancer outcomes in a SEER-Medicare Population. Cancer Epidemiol Biomarkers Prev. 2017;26(11):1603–1610. doi:10.1158/1055-9965.EPI-17-0346
6. Gandini S, Palli D, Spadola G, Bendinelli B, Cocorocchio E, Stanganelli I et al. Anti-hypertensive drugs and skin cancer risk: a review of the literature and meta-analysis. Crit Rev Oncol Hematol. 2018;122:1–9. doi:10.1016/j.critrevonc.2017.12.003
7. Rotshild V, Azoulay L, Zarifeh M, Masarwa R, Hirsh-Raccah B, Perlman A 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(6):555–564. doi:10.1007/s40264-018-0644-4
8. Bangalore S, Kumar S, Kjeldsen SE, Makani H, Grossman E,Wetterslev J et al. Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324 168 participants from randomised trials. Lancet Oncol. 2011;12(1):65–82. doi:10.1016/S1470-2045(10)70260-6
9. Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang JC.Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol. 2010;11(7):627–636. doi:10.1016/S1470-2045(10)70106-6
10. Schmidt SAJ, Schmidt M, Mehnert F, Lemeshow S, Sørensen HT. Use of antihypertensive drugs and risk of skin cancer. J Eur Acad Dermatology Venereol. 2015;29(8):1545–1554. doi:10.1111/jdv.12921
11. Pedersen SA, Johannesdottir Schmidt SA, Hölmich LR, Friis S, Pottegård A, Gaist D. Hydrochlorothiazide use and risk for Merkel cell carcinoma and malignant adnexal skin tumors: a nationwide case-control study. J Am Acad Dermatol. 2019;80 (2):460–465.e9. doi:10.1016/j.jaad.2018.06.014
12. Pottegård A, Pedersen SA, Schmidt SAJ, Hölmich LR, Friis S, Gaist D. Association of hydrochlorothiazide use and risk of malignant melanoma. JAMA Intern Med. 2018;178(8):1120. doi:10.1001/jamainternmed.2018.1652
13. Pedersen SA, Gaist D, Schmidt SAJ, Hölmich LR, Friis S,Pottegård A. Hydrochlorothiazide use and risk of nonmelanoma skin cancer: a nationwide case-control study from Denmark. J Am Acad Dermatol. 2018;78(4):673–681.e9. doi:10.1016/j.jaad.2017.11.042
14. Pottegård A, Hallas J, Olesen M, Svendsen MT, Habel LA, Friedman GD et al. Hydrochlorothiazide use is strongly associated with risk of lip cancer. J Intern Med. 2017;282(4):322–331. doi:10.1111/joim.12629
15. Pottegård A, Friis S, Christensen R dePont, Habel LA,Gagne JJ, Hallas J. Identification of associations between prescribed medications and cancer: a nationwide screening study. EBioMedicine. 2016;7:73–79. doi:10.1016/j.ebiom.2016.03.018
16. Friedman GD, Asgari MM, Warton EM, Chan J, Habel LA.Antihypertensive drugs and lip cancer in non-Hispanic Whites. Arch Intern Med. 2012;172(16):1246. doi:10.1001/archinternmed.2012.2754
17. Friedman GD, Udaltsova N, Chan J, Quesenberry CP, Habel LA, Habel LA. Screening pharmaceuticals for possible carcinogenic effects: initial positive results for drugs not previously screened. Cancer Causes Control. 2009;20(10):1821–1835. doi:10.1007/s10552-009-9375-2
18. Grossman E, Messerli FH, Goldbourt U. Antihypertensive therapy and the risk of malignancies. Eur Heart J. 2001;22 (15):1343–1352. doi:10.1053/euhj.2001.2729
19. Tadic M, Cuspidi C, Belyavskiy E, Grassi G. Intriguing relationship between antihypertensive therapy and cancer. Pharmacol Res. 2019;141:501–511. doi:10.1016/j.phrs.2019.01.037
20. [Electronic resource] Information letter dated 18.01.2019 № 01 И 163/19. URL: http://www.roszdravnadzor.ru/spec/drugs/monitpringlp/documents/56744. In Russian
21. Pharmacovigilance risk assessment committee. PRACrecommendations on signals. Adopted at the 3–6 September 2018PRAC meeting. https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-3–6-september-2018-prac-meeting_en-0.pdf
22. International Agency for Research on Cancer, 2012. IARC monographs on the evaluation of carcinogenic risks to humans. A review of Human Carcinogens. Volume 100 A: Pharmaceuticals. WHO, Lyon, France. https://monographs.iarc.fr/wp-content/uploads/2018/06/mono100A.pdf
23. Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R,Waldron W et al. SEER Cancer Statistics Review, 1975–2007. National Cancer Institute; Bethesda MD: https://seer.cancer.gov/archive/csr/1975_2007/,2010.
24. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002;288(23):2998–3007. doi:10.1001/jama.288.23.2998
25. Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359 (23):2417–2428. doi:10.1056/NEJMoa0806182
26. Tang H, Fu S, Zhai S, Song Y, Han J. Use of antihyper-tensive drugs and risk of malignant melanoma: a meta-analysis of observational studies. Drug Saf. 2018;41(2):161–169. doi:10.1007/s40264-017-0599-x
27. Ruiter R, Visser LE, Eijgelsheim M, Rodenburg EM, Hofman A, Coebergh JW et al. High-ceiling diuretics are associated with an increased risk of basal cell carcinoma in a population-based follow-up study. Eur J Cancer. 2010;46(13):2467–2472. doi:10.1016/j.ejca.2010.04.024
28. Nardone B, Majewski S, Kim AS, Kiguradze T, Martinez-Escala EM, Friedland R et al. Melanoma and non-melanoma skin cancer associated with angiotensin-converting-enzymeinhibitors, angiotensin-receptor blockers and thiazides: a matched cohort study. Drug Saf. 2017;40(3):249–255. doi:10.1007/s40264-016-0487-9
29. Udumyan R, Montgomery S, Fang F, Almroth H, Valdimar-sdottir U, Ekbom A et al. Beta-blocker drug use and survival amongpatients with pancreatic adenocarcinoma. Cancer Res. 2017;77(13):3700–3707. doi:10.1158/0008-5472.CAN-17-0108
30. Jensen AØ, Thomsen HF, Engebjerg MC, Olesen AB, Sørensen HT, Karagas MR. Use of photosensitising diuretics and risk of skin cancer: a population-based case-control study. Br J Cancer. 2008;99(9):1522–1528. doi:10.1038/sj.bjc.6604686
31. Assimes TL, Elstein E, Langleben A, Suissa S. Long-term use of antihypertensive drugs and risk of cancer. Pharmacoepidemiol Drug Saf. 2008;17(11):1039–1049. doi:10.1002/pds.1656
32. Shen J, Huang Y M, Wang M, Hong XZ, Song XN, Zou X et al. Renin-angiotensin system blockade for the risk of cancer and death. J Renin-Angiotensin-Aldosterone Syst. 2016;17(3). doi:10.1177/1470320316656679
33. Pottegård A, Hallas J. New use of prescription drugs prior to a cancer diagnosis. Pharmacoepidemiol Drug Saf. 2017;26 (2):223–227. doi:10.1002/pds.4145
34. Sitas F, Yu XQ, O’Connell DL, Blizzard L, Otahal P, Newman L et al. The relationship between basal and squamous cell skin cancer and smoking related cancers. BMC Res Notes. 2011;4 (1):556. doi:10.1186/1756-0500-4-556
35. Song F, Qureshi AA, Gao X, Li T, Han J. Smoking and risk of skin cancer: a prospective analysis and a meta-analysis. Int J Epidemiol. 2012;41(6):1694–1705. doi:10.1093/ije/dys146
36. Weitkunat R, Sanders E, Lee PN. Meta-analysis of the relation between European and American smokeless tobacco and oral cancer. BMC Public Health. 2007;7:334. doi:10.1186/1471-2458-7-334
37. Gordon R. Skin cancer: an overview of epidemiology and risk factors. Semin Oncol Nurs. 2013;29(3):160–169. doi:10.1016/j.soncn.2013.06.002
38. Iannacone MR, Wang W, Stockwell HG, O’Rourke K, Giuliano AR, Sondak VK et al. Patterns and timing of sunlight exposure and risk of basal cell and squamous cell carcinomas of the skin — a case-control study. BMC Cancer. 2012;12:417. doi:10.1186/1471-2407-12-417
39. Han AY, Kuan EC, Mallen-St Clair J, Alonso JE, Arshi A,St John MA. Epidemiology of squamous cell carcinoma of the lip in the United States. JAMA Otolaryngol Neck Surg. 2016;142 (12):1216. doi:10.1001/jamaoto.2016.3455
40. Bradford PT. Skin cancer in skin of color. Dermatology Nurs. 2009;21(4):170–177. 206; quiz 178.
41. Keller AZ. Cellular types, survival, race, nativity, occupations, habits and associated diseases in the pathogenesis of lip cancers. Am J Epidemiol. 1970;91(5):486–499. doi:10.1093/oxfordjournals.aje.a121159
42. Alberg AJ, Fischer AH. Is a personal history of nonmelanoma skin cancer associated with increased or decreased risk of other cancers? Cancer Epidemiol Biomarkers Prev. 2014;23(3):433–436. doi:10.1158/1055-9965.EPI-13-1309
43. Madan V, Lear JT, Szeimies RM. Non-melanoma skin cancer. Lancet. 2010;375(9715):673–685. doi:10.1016/S0140-6736(09)61196-X
44. Karimi K, Lindgren TH, Koch CA, Brodell RT. Obesity as a risk factor for malignant melanoma and non-melanoma skin cancer. Rev Endocr Metab Disord. 2016;17(3):389–403. doi:10.1007/s11154-016-9393-9
45. Tseng HW, Shiue YL, Tsai KW, Huang WC, Tang PL,Lam HC. Risk of skin cancer in patients with diabetes mellitus. Medicine (Baltimore). 2016;95(26): e4070. doi:10.1097/MD.0000000000004070
46. FDA. S10 Photosafety evaluation of pharmaceuticals guidance for industry. 2015. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmorhttp://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
47. Monteiro AF, Rato M, Martins C. Drug-induced photosen-sitivity: photoallergic and phototoxic reactions. Clin Dermatol. 2016;34(5):571–581. doi:10.1016/j.clindermatol.2016.05.006
48. International Agency for Research on Cancer (IARC). 2017. Monographs on the evaluation of carcinogenic risks to humans. Solar and ultraviolet radiation. https://monographs.iarc.fr/wp-content/uploads/2018/06/mono100D-6.pdf.
49. Boniol M, Autier P, Boyle P, Gandini S. Cutaneous melanoma attributable to sunbed use: systematic review and meta-analysis. BMJ. 2012;345:e4757. doi:10.1136/bmj.e4757
50. Vitiligo Support International. 2017. Photosensitizing medication list. https://www.vitiligosupport.org/newsletters/fall2012/medication.pdf
51. O’Gorman SM, Murphy GM. Photosensitizing medications and photocarcinogenesis. Photodermatol Photoimmunol Photomed. 2014;30(1):8–14. doi:10.1111/phpp.12085
52. Rosenthal T, Gavras I. Angiotensin inhibition and malignan-cies: a review. J Hum Hypertens. 2009;23(10):623–635. doi:10.1038/jhh.2009.21
53. Robinson SN, Zens MS, Perry AE, Spencer SK, Duell EJ, Karagas MR. Photosensitizing agents and the risk of non-melanoma skin cancer: a population-based case-control study. J Invest Dermatol. 2013;133(8):1950–1955. doi:10.1038/jid.2013.33
54. Kaae J, Boyd HA, Hansen AV, Wulf HC, Wohlfahrt J, Melbye M. Photosensitizing medication use and risk of skin cancer. Cancer Epidemiol Biomarkers Prev. 2010;19(11):2942–2949. doi:10.1158/1055-9965.EPI-10-0652
55. Harber LC, Lashinsky AM, Baer RL. Photosensitivity due to chlorothiazide and hydrochlorothiazide. N Engl J Med. 1959;261 (27):1378–1381. doi:10.1056/NEJM195912312612706
56. Torinuki W. Photosensitivity due to hydrochlorothiazide. J Dermatol. 1980;7(4):293–296. doi:10.1111/j.1346-8138.1980.tb01973.x
57. Kunisada M, Masaki T, Ono R, Morinaga H, Nakano E,Yogianti F et al. Hydrochlorothiazide enhances UVA-induced DNA damage. Photochem Photobiol. 2013;89(3):649–654. doi:10.1111/php.12048
58. Pfeifer GP, Besaratinia A. UV wavelength-dependent DNA damage and human non-melanoma and melanoma skin cancer. Photochem Photobiol Sci. 2012;11(1):90–97. doi:10.1039/c1pp05144j
59. Anon Multicentre Trial Group. Hydrochlorothiazide and bendroflumethiazide in low doses — a comparative trial. Acta Pharmacol Toxicol (Copenh). 1984;54 (Suppl1):47–51.
60. Selvaag E, Thune P. Phototoxicity to sulphonamide-derived oral antidiabetics and diuretics: investigations in hairless mice. Photodermatol Photoimmunol Photomed. 1997;13(1–2):4–8. doi:10.1111/j.1600-0781.1997.tb00100.x
61. Beermann B, Groschinsky-Grind M. Pharmacokinetics of hydrochlorothiazide in man. Eur J Clin Pharmacol. 1977;12 (4):297–303.
62. Borgström L, Johansson CG, Larsson H, Lenander R.Pharmacokinetics of bendroflumethiazide after low oral doses. J Pharmacokinet Biopharm. 1981;9(4):431–441.
63. Health Canada. Health Product InfoWatch — January 2019. Review article: Prolonged use of hydrochlorthiazide and the risk of non-melanoma skin cancer. https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/health-product-infowatch/health-product-infowatch-january-2019.html#s5–1.
64. Faconti L, Ferro A, Webb AJ, Cruickshank JK, Chowien-czyk PJ, British and Irish Hypertension Society. Hydrochlorothiazide and the risk of skin cancer. A scientific statement of the British and Irish Hypertension Society. J Hum Hypertens. 2019;33(4):257–258. doi:10.1038/s41371-019-0190-2
65. [Electronic resource] Melanoma skin cancer statistics. CancerResearch UK. URL: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/melanoma-skin-cancer.
66. [Electronic resource] Overview. Hypertension in adults: diagnosis and management. Guidance. NICE. URL: https://www.nice.org.uk/guidance/cg127.
67. Whelton PK, Carey RM, Aronow WS Casey DE, Collins KJ,Himmelfarb CD et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation and management of high blood pressure in adults. J Am Coll Cardiol. 2018;71(19): e127–e248. doi:10.1016/j.jacc.2017.11.006
68. [Electronic resource] The opinion of the experts of the Russian Cardiology Society on hydrochlorothiazide “Balanced decision on long-term use of diuretics in clinical practice”. URL: https://scardio.ru/news/novosti_obschestva/mnenie_ekspertov_rko_po_situacii_s_gidrohlorotiazidom_vzveshennoe_otnoshenie_po_dlitelnomu_primeneniyu_diuretikov_v_terapevticheskoy_praktike/. In Russian.
Review
For citations:
Kobalava Zh.D., Kokhan E.V., Kiyakbaev G.K. Hydrochlorothiazide and the risk of non-melanoma skin cancer: a critical review. "Arterial’naya Gipertenziya" ("Arterial Hypertension"). 2019;25(4):376-388. (In Russ.) https://doi.org/10.18705/1607-419X-2019-25-4-376-388