Abstract
Cancer and cardiovascular (CVD) diseases are leading public health problems. Among patients diagnosed with cancer, the 5-year relative survival rate has increased significantly, primarily as a result of advances in cancer treatment. However, the drugs used for cancer chemotherapy are cardiotoxic and shorten the average life expectancy despite effective cancer treatment. In this regard, anthracyclines (anti-tumor antibiotics) are noteworthy, which are successfully used in the chemotherapy of lymphomas, solid tumors and certain types of breast cancer. Cardio-toxicity of anthracyclines and their management remains an important challenge in cancer therapy, due to their cytotoxic mechanisms. Different definitions of chemotherapy-induced cardiotoxicity are used, leading to inconsistencies in the diagnosis and management of the disease. Based on the need to harmonize and refine the definition, a new definition of cancer therapy-related cardiovascular toxicity (CTR-CVT) was developed. In this article, we review the modern aspects related to cancer chemotherapy: definition of cardiotoxicity, pathogenesis, ways of prevention and treatment.
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4. PMID: 33538338.
Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Incidence-SEER 18 Registries Research Data + Hurricane Katrina Impacted Louisiana Cases, November 2020 Submission (2000-2018) -Linked To County Attributes-Total U.S., 1969-2018 Counties. National Cancer Institute, Division of Cancer Control and Population Sciences, Surveillance Research Program, Surveillance Systems Branch; 2021
დაავადებათა კონტროლის და საზოგადოებრივი ჯანმრთელობის ეროვნული ცენტრი; ავთვისებიანი სიმსივნეები საქართველოში 2015-2021. https://ncdc.ge/#/pages/file/7bb73fc7-12bc-4b09-a18a-7b17b9cace94
On behalf of the American Heart Association Cardiovascular Disease in Women and Special Populations Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research. Originally published1 Feb 2018 https://doi.org/10.1161/CIR.0000000000000556 Circulation. 2018;137:e30–e660
Amstrong GT, Oeffinger KC, Chen Y, Kawashima T, Yasui Y, Leisenring W, Stovall M, Chow EJ, Sklar CA, Mulrooney DA, Mertens AC, Border W, Durand JB, Robison LL, Meacham LR. Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol 2013;31: 3673–3680.
Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments. Nat Rev Cardiol 2015;12:620 7. Hong, R. A., Iimura, T., Sumida, K. N. & Eager, R. M. Cardiooncology/oncocardiology. Clin. Cardiol. 12, 733–737 (2010).
M. Y. Su, L. Y. Lin, and Y. H. Tseng, “CMR-verified56 diffuse myocardial fibrosis is associated with diastolic dysfunction in HFpEF,” JACC: Cardiovascular Imaging,2014; 7(10):991–997.
Cascales A, Pastor-Quirante F, Sánchez-Vega B, Luengo-Gil G, Corral J, Ortuño-Pacheco G, Vicente V, de la Peña FA. Association of anthracycline-related cardiac histological lesions with NADPH oxidase functional polymorphisms. Oncologist. 2013;18(4):446-53..
D. Cardinale, A. Colombo, G. Lamantia et al., “Anthracyclineinduced cardiomyopathy: clinical relevance and response to pharmacologic therapy,” Journal of the American College of Cardiology: 2010, 55( 3): 213–220.
Henriksen PA. Anthracycline cardiotoxicity: an update on mechanisms, monitoring and prevention. Heart. 2018 Jun;104(12):971-7.
Okwuosa TM, Keramida K, Filippatos G, Yancy CW. Cancer therapy and the heart; the necessity to calibrate risk. Eur J Heart Fail. 2020 Nov;22(11):1961-1965. doi: 10.1002/ ejhf.1999. Epub 2020 Sep 29. PMID: 32892435. https:// www.webmd.com/breast-cancer/breast-cancer-anthracyclines
Marzia Lotrionte, Giuseppe Biondi-Zoccai, Antonio Abbate, Gaetano Lanzetta, Fabrizio D’Ascenzo, Vincenzo Malavasi, Mariangela Peruzzi, Giacomo Frati, Giovanni Palazzoni, Review and Meta-Analysis of Incidence and Clinical Predictors of Anthracycline Cardiotoxicity, The American Journal of Cardiology, Volume 112, Issue 12, 2013, Pages 1980-1984, ISSN 0002-9149, https://doi.org/10.1016/j.amjcard.2013.08.026.
რ. ღვამიჩავა, მ.შავდია. ონკოლოგია, თბილისი,2010, 674 გვ.
Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents. Drug safety. 2000;22(4):263-302
Pommier Y, Leo E, Zhang H, Marchand C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chemistry & biology. 2010;17(5):421-33
Visone V, Szabó I, Perugino G, Hudecz F, Bánóczi Z, Valenti A. Topoisomerases inhibition and DNA binding mode of daunomycin–oligoarginine conjugate. Journal of enzyme inhibition and medicinal chemistry. 2020;35(1):1363-71
Shandilya, M. , Sharma, S. , Das, P. P. , Charak, S. . Molecular-Level Understanding of the Anticancer Action Mechanism of Anthracyclines. In: Arnouk, H. , Hassan, B. A. R. , editors. Advances in Precision Medicine Oncology, London: Intech Open; 2020 [cited 2022 Oct 26]. doi: 10.5772/intechopen.94180
Coldwell KE, Cutts SM, Ognibene TJ, Henderson PT, Phillips DR. Detection of Adriamycin–DNA adducts by accelerator mass spectrometry at clinically relevant Adriamycin concentrations. Nucleic acids research. 2008;36(16):e100
Russo, M., Della Sala, A., Tocchetti, C.G. et al. Metabolic Aspects of Anthracycline Cardiotoxicity. Curr. Treat. Options in Oncol. 22, 18 (2021). https://doi.org/10.1007/ s11864-020-00812-1
Goodman J, Hochstein P: Generation of free radicals and lipid peroxidation by redox cycling of adriamycin and daunomycin. Biochem Biophys Res Commun, 1977, 77, 797–803
Bachur NR. Anthracycline antibiotic pharmacology and metabolism. Cancer Treat Rep. 1979;63(8):7-820
Zhang S, Liu X, Bawa-Khalfe T, Lu LS, Lyu YL, Liu LF, et al. Identification of the molecular basis of doxorubicininduced cardiotoxicity. Nat Med. (2012) 18:1639–42. doi: 10.1038/nm.2919
Koleini N, Kardami E. Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity. Oncotarget. 2017;8(28):46663–80. https://doi.org/10.18632/oncotarget.16944.
Goormaghtigh E, Chatelain P, Caspers J, Ruysschaert JM. Evidence of a complex between adriamycin derivatives and cardiolipin: possible role in cardiotoxicity. Biochem Pharmacol. 1980;29(21):3003–10. https://doi.org/10.1016/0006-2952(80)90050-7.
Bertero E, Maack C. Metabolic remodelling in heart failure. Broad overview of the physiological processes of cardiac energy metabolism and their pathological alterations in heart failure. Nat Rev Cardiol. 2018;15(8):457–70. https:// doi.org/10.1038/s41569-018-0044-6
McGarrah RW, Crown SB, Zhang GF, Shah SH, Newgard CB. Discuss the current state of metabolomics, one of the newer omics technologies, emerged as a powerful tool for understanding the metabolic changes that occur in heart failure and ischemic heart disease. Cardiovascular metabolomics. Circ Res. 2018;122(9):123858. https://doi.org/10.1161/ CIRCRESAHA.117.311002
Daniela Cardinale, Fabiani Iacopo and Carlo Maria Cipolla Cardiotoxicity of Anthracyclines Front. Cardiovasc. Med., 18 March 2020. Cardio-Oncology https://doi.org/10.3389/fcvm.2020.00026
Neilan TG, Coelho-Filho OR, Pena-Herrera D, Shah RV, Jerosch-Herold M, Francis SA, Moslehi J, Kwong RY. Left ventricular mass in patients with a cardiomyopathy after treatment with anthracyclines. Am J Cardiol. 2012;110:1679–1686.
Jordan JH, Castellino SM, Meléndez GC, Klepin HD, Ellis LR, Lamar Z, Vasu S, Kitzman DW, Ntim WO, Brubaker PH, Reichek N, D’Agostino RB Jr, Hundley WG. Left ventricular mass change after anthracycline chemotherapy. Circ Heart Fail. 2018;11:e004560.
Sawyer DB, Peng X, Chen B, Pentassuglia L, Lim CC. Mechanisms of anthracycline cardiac injury: can we identify strategies for cardioprotection? Prog Cardiovasc Dis. 2010;53:105–113.
Amanda J. Favreau-Lessard, PhD, Douglas B. Saw- yer, MD, PhD, and Sanjeev A. Francis, MD. Anthracycline Cardiomyopathy,The Plot Gets Thinner. Circulation: Heart Failure.2018 July:11(7):1-3
Alexander R Lyon, Teresa López-Fernández, Liam S Couch, Riccardo Asteggiano, Marianne C Aznar, Jutta Bergler-Klein, Giuseppe Boriani, et.al 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS): Developed by the task force on cardio-oncology of the European Society of Cardiology (ESC), European Heart Journal, Volume 43, Issue 41, 1 November 2022, Pages 4229–4361, https://doi.org/ 10.1093/eurheartj/ehac244
Kourek, C.; Touloupaki, M.; Rempakos, A.; Loritis, K.; Tsougkos, E.; Paraskevaidis, I.; Briasoulis, A. Cardioprotective Strategies from Cardiotoxicity in Cancer Patients: A Comprehensive Review. J. Cardiovasc. Dev.Dis.2022,9,259. https:// doi.org/10.3390/jcdd9080259
Shapira J, Gotfried M, Lishner M, Ravid M. Reduced cardiotoxicity of doxorubicin by a 6-hour infusion regimen. A prospective randomized evaluation. Cancer 1990;65:870–873
Curigliano G, Cardinale D, Dent S, Criscitiello C, Aseyev O, Lenihan D, et al. Cardiotoxicity of anticancer treatments: epidemiology, detection, and management. CA Cancer J Clin. (2016) 66:309–25. doi: 10.3322/caac.21341
Bloom MW, Hamo CE, Cardinale D, Ky B, Nohria A, Baer L, et al. Cancer therapy-related cardiac dysfunction and heart failure: part 1: definitions, pathophysiology, risk factors, and imaging. Circ Heart Fail. (2016) 9:e002661. doi: 10.1161/CIRCHEARTFAILURE.115.002661
Lao J, Madani J, Puértolas T, Alvarez M, Hernández A, Pazo-Cid R, et al. Liposomal doxorubicin in the treatment of breast cancer patients: a review. J Drug Deliv. 2013; 2013: 456409 10.1155/2013/456409
Rochlitz C, Ruhstaller T, Lerch S, Spirig C, Huober J, Suter T, et al. Combination of bevacizumab and 2-weekly pegylated liposomal doxorubicin as first-line therapy for locally recurrent or metastatic breast cancer. A multicenter, single-arm phase II trial (SAKK 24/06). Ann Oncol. 2011; 22: 80– 85. 10.1093/annonc/mdq319
Harris L, Batist G, Belt R, Rovira D, Navari R, Azarnia N, et al. Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer. 2002; 94: 25–36
Sparano JA, Makhson AN, Semiglazov VF, Tjulandin SA, Balashova OI, Bondarenko IN, et al. Pegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel monotherapy in patients with advanced breast cancer previously treated with neoadjuvant-adjuvant anthracycline therapy: results from a randomized phase III study. J Clin Oncol. 2009; 27: 4522–4529. 10.1200/JCO.2008.20.5013
Waterhouse DN, Tardi PG, Mayer LD, Bally MB. A comparison of liposomal for- mulations of doxorubicin with drug administered in free form: changing toxicity profiles. Drug Saf 2001;24:903–920.
Vejpongsa P, Yeh ETH. Prevention of anthracyclineinduced cardiotoxicity: challenges and opportunities. J Am Coll Cardiol 2014;64:938–945.
Yamaguchi N, Fujii T, Aoi S, Kozuch PS, Hortobagyi GN, Blum RH. Comparison of cardiac events associated with liposomal doxorubicin, epirubicin and doxorubicin in breast cancer: a Bayesian network meta-analysis. Eur J Cancer 2015;51:2314–2320.
Batist G, Ramakrishnan G, Rao CS, Chandrasekharan A, Gutheil J, Guthrie T, et al. Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J Clin Oncol. 2011; 19: 1444–1454.
Kloner RA, Jennings RB. Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 2. Circulation.2001;104:3158-3167.
Cardinale D, Colombo A, Lamantia G, et al. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol.2010;55:213-220.
Lipshultz SE. Dexrazoxane for protection against cardiotoxic effects of anthracyclines in children. J Clin Oncol 1996;14:328-331
Speyer JL, Green MD, Kramer E, et al. Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med1988;319:745-752
The ASCO guidelines for the use of chemotherapy and radiotherapy protectants: a critique. J Clin Oncol2000;18:2004-2006
Yusuf S, Pitt B, Davis CE, Hood WB Jr, Cohn JN; Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. SOLVD Investigators, N Engl J Med. 1992;327(10):685.
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of. Eur Heart J. 2016;37:2129–200.
Cadeddu C, Piras A, Mantovani G, Deidda M, Dessì M, Madeddu C, Massa E, Mercuro G (2010) Protective effects of the angiotensin II receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress, and early ventricular impairment. Am Heart J 160(3):487.e481–487. https://doi.org/10.1016/j.ahj.2010.05.037
Dessì M, Madeddu C, Piras A, Cadeddu C, Antoni G, Mercuro G, Mantovani G (2013) Long-term, up to 18 months, protective effects of the angiotensin II receptor blocker telmisartan on Epirubin-induced inflammation and oxidative stress assessed by serial strain rate. Springerplus 2(1):198. https://doi.org/10.1186/2193-1801-2-198
Georgakopoulos P, Roussou P, Matsakas E, Karavi- das A, Anagnostopoulos N, Marinakis T, Galanopoulos A, Georgiakodis F, Zimeras S, Kyriakidis M, Ahimastos A (2010) Cardioprotective effect of metoprolol and enalapril in doxorubicin-treated lymphoma patients: a prospective, parallelgroup, randomized, controlled study with 36-month followup. Am J Hematol 85(11):894-896. https://doi.org/10.1002/ ajh.21840
Bosch X, Esteve J, Sitges M, de Caralt TM, Domènech A, Ortiz JT, Monzó M, Morales-Ruiz M, Perea RJ, Rovira M (2011) Prevention of chemotherapy-induced left ventricular dysfunction with enalapril and carvedilol: rationale and design of the OVERCOME trial.J Card Fail 17(8):643–648. ht- tps://doi.org/10.1016/j.cardfail.2011.03.008
Kalam K, Marwick TH. Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: a systematic review and meta-analysis. Eur J Cancer. 2013;49:2900-2909.
Kalay N, Basar E, Ozdogru I, et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol. 2006;48:2258-2262.
De Nigris F,Rienzo M, Schiano C, Fiorito C, Casamassimi A,Napoli C, Prominent cardioprotective effects of third generation beta blocker nebivolol against anthracycline-induced cardiotoxicity using the model of isolated perfused rat heart. Eur J Cancer. 2008; 44: 334-340
Lee MMY, Sattar N, McMurray JJV, Packard CJ. Statins in the Prevention and Treatment of Heart Failure: a Review of the Evidence. Curr Atheroscler Rep. 2019 Jul 27;21(10):41. doi: 10.1007/s11883-019-0800-z. PMID: 31350612; PMCID: PMC6660504.
Seicean S, Seicean A, Plana JC, Budd GT, Marwick TH. Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study. J Am Coll Cardiol. 2012;60:2384-2390.
Acar Z, Kale A, Turgut M, et al. Efficiency of atorvastatin in the protection of anthracycline-induced cardiomyopathy. J Am Coll Cardiol. 2011;58:988-989.
Shanliang Zhong, Xiaohui Zhang, Lin Chen, Tengfei Ma, Jinhai Tang, Jianhua Zhao, Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies, Cancer Treatment Reviews, Volume 41, Issue 6, 2015,Pages 554-567, ISSN 0305-7372, https://doi.org/10.1016/j.ctrv.2015.04.005.
Miller AB. Aldosterone antagonism in heart failure. Vasc Health Risk Manag. 2007;3(5):605-9. PMID: 18078011; PMCID: PMC2291304.
Akpek M, Ozdogru I, Sahin O, Inanc M, Dogan A, Yazici C, Berk V, Karaca H, Kalay N, Oguzhan A, Ergin A. Protective effects of spironolactone against anthracyclineinduced cardiomyopathy. Eur J Heart Fail. 2015 Jan;17(1):81-9. doi: 10.1002/ejhf.196. Epub 2014 Nov 20. PMID: 25410653