Cancer Therapy-Induced Cardiotoxicity: Where are We Now?

1. Introduction

Cardiovascular diseases (CVDs) are the leading cause of death. According to the World Health Organization (WHO), an estimated 17 million people die each year of CVDs, which corresponds to approximately 30% of all deaths worldwide [1]. Cancer is the second cause of death globally, being associated with the deaths of nearly nine million individuals each year [2]. Unfortunately, the incidence of cancer is expected to rise by about 70% over the next two decades, according to the WHO [3]. Today, 50% of those initially diagnosed with cancer survive for at least 10 years, but according to some experts, this survival rate should increase significantly in the future [4,5]. For these reasons, the number of cancer survivors expected to develop secondary conditions and life-threatening diseases associated with cancer drugs or radiotherapies will also increase. According to some researchers, this relatively new unmet medical need of chemotherapy- and radiotherapy-induced CVDs is bound to reach epidemic proportions in the near future [5, 6].

2. Cardioprotective Drugs

Anthracyclines (e.g. doxorubicin, epirubicin, daunorubicin, idarubicin) are among the first cancer drugs to be identified as medicines leading to increased risk of CVDs. They are antibiotics derived from Streptomyces and have been widely used for more than 50 years against leukemia, lymphoma, and breast, stomach, uterine, ovarian, bladder, and lung cancers [7]. Daunorubicin, one of the first anthracyclines to be used, was reported in the late 60s to induce significant adverse cardiac events, including cardiomyopathies and cardiac failures in children [8]. Dose-dependent/agent-specific cardiotoxicity is now generally considered a significant medical concern [9]. In child cancer survivors, some statistics report incidences of asymptomatic myocardial dysfunction ranging from 18 to 57%, with 5% suffering heart failure problems [10]. Comparable risks of heart failure were found with doxorubicin at a dose of 400 mg/m2, and exponentially increasing risks at doses above 500 mg/m2 [11]. Other studies indicate that cancer survivors have 15-fold greater risks of experiencing congestive heart failure and 10-fold higher rates of CVDs [12,13]. Furthermore, higher risks of cardiovascular morbidity and mortality may persist up to 45 years post-chemotherapy or radiotherapy [14,15]. Radiation-induced CVDs are also well-recognized. In the case of breast cancer for instance, radiotherapy has been clearly associated with myocardial fibrosis and cardiomyopathy, coronary artery disease, valvular disease, pericardial disease, and arrhythmias [43].

Anthracyclines are still today considered among the most efficient drugs currently available against most types of cancer. Of course, other drugs could be used to avoid cardiomyopathies and heart failures, but none of these alternatives have clearly been shown not to induce CVDs (see Table 1). In fact, a detailed list of all cancer drugs and their associated risks of CVDs is lacking. However, we know that alkylating agents (cyclophosphamide, ifosfamide), platinum agents, antimetabolites (5-fluorouracil, capecitabine), antibiotics (mitoxantrone, mitomycin, bleomycin), and antimicrotubule agents (taxanes) can all cause heart disease [16]. We also know that hypertension may be induced by some chemotherapeutic agents such as angiogenesis inhibitors (17%?80%), alkylating agents (36%?39%), and immunosuppressants after stem-cell transplantation (30%?80%) [17,18]. Angiogenesis inhibitors known as vascular signaling pathway inhibitors and anti-vascular endothelial growth factor antibodies (e.g. bevacizumab and certain tyrosine kinase inhibitors such as sunitinib, sorafenib, and pazopanib) are also clearly associated with hypertension. The incidence of de novo or worsening hypertension in association with these drugs varies between 17% and 80% [19].

Table 1: List of current standard cancer drugs with evidence or lack of evidence of CVDs

Regarding mechanisms, many questions remain. Nonetheless, there is compelling evidence suggesting that various pathophysiological mechanisms exist, and that each family of cancer drugs affects heart functions through specific actions upon these different mechanisms. Some of the proposed mechanisms include: 1) direct cellular toxicity, with a cumulative myocardial injury, resulting in both diastolic and systolic dysfunction; 2) effects on the coagulation system, resulting in ischemic events, thrombogenesis and vascular toxicity; 3) arrhythmogenic effects; 4) hypertensive effects; 5) myocardial and/or pericardial inflammation associated with myocardial dysfunction or pericardial sequels [45].

Physical activity and at least one cardioprotective agent, dexrazoxane, have been shown to prevent and mitigate cardiotoxicity (although not safely in the case of dexrazoxane, according to the restricted use notice released in 2011) [20,44], but additional studies are urgently needed to understand further the pathophysiology of chemotherapy-induced cardiotoxicity, and to explore safe and potent combination therapies capable of treating cancer while preventing CVDs.

According to the National Cancer Institute, two hundred different drugs have been approved in the US for use against cancer (www.cancer.gov). They belong to different families and a wide variety of subtypes based on chemical structure and physiological actions or targets, but the alkylating drugs, antimetabolites, and natural products constitute the main families of drugs against cancer. As of today, several of them have clearly been associated with CVDs, either based on results in dissociated cells, animal models, or patients (Table 1).

Several populations are at risk of further developing CVDs. Children are among the first groups identified to suffer specifically from chemotherapy-induced CVDs [8] and secondary acute myeloid leukemia and myelodysplactic syndrome following combination therapy with anthracyclines and dexrazoxane. CVDs also occur with greater incidence in people with a spinal cord injury or multiple sclerosis [21, 22]. Chronic spinal cord injury has also been associated with greater incidence of some cancers (e.g. bladder, esophageal, liver, and hematologic cancer) [23, 24]. People suffering from obesity and type 2 diabetes are obviously also at risk of CDVs. Actually, the first risk factors of CVDs are overweight, weight fluctuations, and related lack of physical exercise [25; see also www.world-heart-federation.org]. People at risk also include the elderly and those smoking or excessively drinking alcohol, as well as those with high levels of LDL cholesterol, triglycerides and/or hypertension [27].

In the future, several avenues should be explored by physicians and scientists. Healthcare professionals should expand and extend long-term surveillance and pharmacovigilance (i.e. greater than the five years post-treatment milestone) associated with CVDs to further document the incidence, prevalence and subpopulations most at risk. Biomedical experts and other scientists should focus on unraveling new mechanisms and cellular targets, enabling the identification of innovative solutions and alternative drug candidates. Given that chemotherapy-induced cardiotoxicity should still be considered an unmet medical need, the industry should increase efforts and investments in R&D activities for the clinical development of new candidate products. In the meantime, healthcare professionals should attempt to prevent cardiotoxicity by screening for risk factors, monitoring for signs and symptoms during chemotherapy, and continuing follow-up that may include electrocardiographic and echocardiographic studies, angiography, and measurements of biochemical markers of myocardial injury.

Conflict of Interest

None declared

References

1. Balukumar P, Maung-U K, Jagadeesh G. Prevalence and prevention of cardiovascular disease and diabetes mellitus. Pharmacol Res 113 (2016): 600-609.
2. Leal YA, Fernadez-Garrote LM, Mohar-Betancourt A, Meneses-Garcia A. The importance of registries in cancer control. Salud Publica Mex 58 (2016): 309-316.
3. http://www.who.int/mediacentre/factsheets/fs297/en/
4. Lucas G, Marcu A, Piano M, Grosvenor W, Mold F, et al. Cancer survivors’ experience with telehealth: a systematic review and thematic synthesis. J Med Internet Res 19 (2017): e11.
5. http://www.cancerresearchuk.org/
6. Thavendiranathan P, Nolan MT. An emerging epidemic: cancer and heart failure. Clinical Science 131 (2016): 113-121.
7. Fujiwara A, Hoshino T, Westley JM. Anthracycline antibiotics. Critical Reviews in Biotechnology 3 (1985): 133-157.
8. Laine JL, Julienne O, Leroy J, Lamagnère JP, Laugier J, et al. Cardiac toxicity of rubidomycin. Apropos of two cases. Pédiatrie (French) 28 (1973): 201-210.
9. Mele D, Nardozza M, Spallarossa P, Frassoldati A, Tocchetti CG, et al. Current views on anthracycline cardiotoxicity. Heart Fail Rev 21 (2016): 621-634.
10. Kucharska W, Negrusz-kawecka M, Gromkowska M. Cardiotoxicity of oncological treatment in children. Adv Clin Exp Med 21 (2012): 281-288.
11. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97 (2003):2869-2879.
12. Menna P, Salvatorelli E, Minotti G.Cardiotoxicity of antitumor drugs. Chem Res Toxicol 21 (2008): 978-989.
13. Cardinale D, Bacchiani G, Beggiato M, et al. Strategies to prevent and treat cardiovascular risk in cancer patients. Semin Oncol 40 (2013): 186-198.
14. Reulen RC, Winter DL, Frobisher C, et al. Long-term cause-specific mortality among survivors of childhood cancer. JAMA 304 (2010): 172-179.
15. Salvatorelli E, Menna P, Minotti G. Managing anthracycline-induced cardiotoxicity: beginning with the end in mind. Future Cardiology 11 (2015): 363-366.
16. Madeddu C, Deidda M, Piras A, Cadeddu C, Demurtas L, et al. Pathophysiology of cardiotoxicity induced by nonanthracycline chemotherapy. J Cardiovascu Med 17 (2016): 12-18.
17. Maitland ML, Bakris GL, Black HR, Chen HX, Durand J-B, et al. Cardiovascular Toxicities Panel, convened by the Angiogenesis Task Force of the National Cancer Institute Investigational Drug Steering Committee. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J Natl Cancer Inst 102 (2010): 596-604.
18. Bursztyn M, Zelig O, Or R, Nagler A. Isradipine for the prevention of cyclosporine-induced hypertension in allogeneic bone marrow transplant recipients: a randomized, double-blind study. Transplantation 63 (1997): 1034-1036.
19. Mouhayar E, Salahudeen A. Hypertension in cancer patients. Tex Heart Inst J 38 (2011): 263-265.
20. Chen JJ, Wu PT, Middlekauff HR, Nguyen KL. Aerobic Exercise in Anthracycline-Induced Cardiotoxicity: A Systematic Review of Current Evidence and Future Directions. Am J Physiol Heart Circ Physiol 312 (2017): H213-H222.
21. Hagen EM, Rekand T, Gronning M, Faerestrand S. Cardiovascular complications of spinal cord injury. Tidsskr Nor Laegeforen 132 (2012): 1115-1120.
22. Roshanisefat H, Bahmanyar S, Hillert J, Olsson T, Montgomery S. Multiple sclerosis clinical course and cardiovascular disease risk?Swedish cohort study. Eur J Neurol 21 (2014): 1353-1388.
23. Kalisvaart JF, Katsumi HK, Ronningen LD, Hovey RM. Bladder cancer in spinal cord injury patients. Spinal Cord 48 (2010): 257-261.
24. Chia-Hong Kao, Li-Min Sun, Yueh-Sheng Chen, Cheng-Li Lin, Ji-An Liang, et al. Risk of Nongenitourinary Cancers in Patients with Spinal Cord Injury-A Population-based Cohort Study. Medicine 95 (2016): e2462.
25. Bangalore S, Fayyad R, Laskey R, DeMicco DA, Messerli FH, et al. Body-weight fluctuations and outcomes in coronary disease. N Engl J Med 376 (2017): 1332-1340.
26. Marz W, Kleber ME, Scharnagl H, Speer T et al. HDL cholesterol: reappraisal of its clinical relevance. Clin Res Cardiol 24 (2017): 1-13.
27. Collins DR, Tompson AC, Onakpova IJ, Roberts N et al. Global cardiovascular risk assessment in the primary prevention of cardiovascular disease in adults: systematic review of systematic reviews. BMJ Open 7 (2017): e013650.
28. Yanamandra U, Gupta S, Khadwal A, Malhotra P. Melphalan-induced cardiotoxicity: ventricular arrhythmias. BMJ Case Rep. 2016 Dec 15;2016.
29. Avci H, Epikmen ET, Ipek E, Tunca R, Birincioglu SS, et al. Protective effects of silymarin and curcumin on cyclophosphamide-induced cardiotoxicity. Exp Toxicol Pathol 2017
30. Madeddu C, Deidda M, Piras A, Cadeddu C, Demurtas L, et al. Pathophysiology of cardiotoxicity induced by nonanthracycline chemotherapy. J Cardiovasc Med 17 (2016): S12-S18.
31. Simbre VC, Duffy SA, Dadlani GH, Miller TL, Lipshultz SE. Cardiotoxicity of cancer chemotherapy: implications for children. Paediatr Drugs 7 (2005) :187-202.
32. Brestescher C, Pautier P, Farge D. Chemotherapy and cardiotoxicity. Ann Cardiol Angeiol 44 (1995): 443-447.
33. Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf 22 (2000): 263-302.
34. Najam R, Bano N, Mirza T, Hassan S. Adverse effects on cardiovascular status and lipid levels of albino Wistar rats treated with cisplatin and oxaliplatin in combination with 5 Fluorouracil. Pak J Pharm Sci 27 (2014): 1409-1418.
35. Ryberg M, Nielsen D, Skovsgaard T, Hansen J, Jensen BV, et al. Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer. J Clin Oncol 16 (1998): 3502-3508.
36. Löw-Friedrich I, von Bredow F, Schoeppe W. In vitro studies on the cardiotoxicity of chemotherapeutics. In vitro studies on the cardiotoxicity of chemotherapeutics. Chemotherapy 36 (1990): 416-421.
37. Ozturk B, Tacoy G, Coskun U, Yaman E, Sahin G, et al. Gemcitabine-induced acute coronary syndrome: a case report. Med Princ Pract 18 (2009): 76-80.
38. Zhao L, Zhang B. Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes. Sci Rep 7 (2017): 44735.
39. Gros R, Hugon V, Thouret JM, Peigne V. Coronary Spasm after an Injection of Vincristine. Chemotherapy 62 (2017): 169-171.
40. Le Brun-Ly V, Martin J, Venat-Bouvet L, Darodes N, Labourey JL, et al. Cardiac toxicity with capecitabine, vinorelbine and trastuzumab therapy: case report and review of fluoropyrimidine-related cardiotoxicity. Oncology 76 (2009): 322-325.
41. Li C, Qu X, Xu W, Qu N, Mei L, et al. Arsenic trioxide induces cardiac fibroblast apoptosis in vitro and in vivo by up-regulating TGF-?1 expression. Toxicol Lett 219 (2013): 223-230.
42. Ito A, Kimura T, Miyoshi S, Ogawa S, Arai T. Photosensitization reaction-induced acute electrophysiological cell response of rat myocardial cells in short loading periods of talaporfin sodium or porfimer sodium. Photochem Photobiol 87 (2011): 199-207.
43. Taunk NK, Haffty BG, Kostis JB, Goyal S. Radiotherapy-induced heart disease : pathologic abnormalities and putative mechanisms. Front Oncol 5 (2015): 1-8.
44. http://www.fda.gov/Drugs/DrugSafety/ucm263729.htm
45. Florescu M, Cinteza M, Vinereanu D. Chemotherapy-induced cardiotoxicity. Maedica 8 (2013): 59-67.