The dawn of a new era in onco-cardiology: The ...

International Journal of Cardiology 220 (2016) 837–841

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The dawn of a new era in onco-cardiology: The Kumamoto Classification Daisuke Sueta, Noriaki Tabata, Tomonori Akasaka, Takayoshi Yamashita, Tomokazu Ikemoto, Seiji Hokimoto ⁎ Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

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Article history: Received 19 May 2016 Accepted 29 June 2016 Available online 01 July 2016 Keywords: Onco-cardiology Classification

a b s t r a c t The term “onco-cardiology” has been used in reference to cardiotoxicity in the treatment of malignant disease. In actual clinical situations, however, cardiovascular disease (CVD) associated with malignant disease and the concurrence of atherosclerotic disease with malignant disease are commonly observed, complicating the course of treatment. Patients with malignant disease associated with coronary artery disease often die from the cardiovascular disease, so it is essential to classify these disease states. Additionally, the prevalence of these classifications makes it easy to manage patients with malignant disease and coronary artery disease. We divided the broad field of onco-cardiology into 4 classifications based on clinical scenarios (CSs): CS1 represents the so-called paraneoplastic syndrome. CS2 represents cardiotoxicity during treatment of malignant diseases. CS3 represents the concurrence of atherosclerotic disease with malignant disease, and CS4 represents cardiovascular disease with benign tumors. This classification facilitates the management of patients with malignant disease and coronary artery disease by promoting not only the primary but also the secondary prevention of CVD. © 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Onco-cardiology is a new field of clinical medicine that addresses the overlap between cardiovascular and malignant disease. While the incidence of malignant disease continues to increase, the complete resolution rate and cure rate have improved due to recent advances in treatment, especially chemotherapy. As a result, the adverse effects of these drugs are becoming a major factor affecting the prognosis and quality of life of survivors of malignant disease. Onco-cardiology is associated with many clinical situations. [1] In particular, while some drugs, such as anthracycline, have long been known to promote cardiotoxicity, the adverse effects of a variety of molecular targeted drugs on the cardiovascular system have not been well studied. The mean times to diagnosis (MTTD) are improving, but cardiovascular complications are increasing. This may be attributable to an aging society, in which increases in malignant disease and cardiovascular disease are expected. With the introduction of molecular-targeted therapeutic drugs, which are currently in development, it is expected that cardiovascular complications due to chemotherapy will increase as the incidences of malignant disease, heart disease, and cerebrovascular disease increase. Malignant disease can also develop from lifestyle-related diseases. For example, the report of a joint World Health Organization/Food and Agriculture Organization Expert Consultation concluded that overweight and obesity are established risk factors for adenocarcinoma of ⁎ Corresponding author at: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. E-mail address: [email protected] (S. Hokimoto).

http://dx.doi.org/10.1016/j.ijcard.2016.06.330 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.

the esophagus [2], gastric cancer is associated with salt intake [3] and diet-related factors may account for up to 80% of the differences in the rates of colorectal cancer between different countries [4]. (World Health Organization, 2003) Therefore, atherosclerotic diseases are often present, which complicates treatment [5,6]. Currently, research on onco-cardiology has focused on the myocardial damage induced by chemotherapeutic drugs for malignant tumors. The comorbidity rates, the concomitant factors, and the relationship between malignant disease and atherosclerotic disease are not well understood [7–9]. We previously reported the association between malignancy and ischemic heart disease from the perspective of coronary artery calcification as a new aspect of onco-cardiology [10]. Onco-cardiology research has historically focused on cardiotoxicity; no studies available in the literature have systematically classified the relationship between traditional cardiovascular risk factors and the development of malignant disease [11]. Because patients with malignant disease and coronary artery diseases are more likely to die from cardiovascular disease than malignant disease, an appropriate classification system is extremely important. These classifications will facilitate the management of malignant disease in patients with coronary artery diseases as a secondary preventive measure. Therefore, in this paper, we propose a classification system based on various clinical scenarios (CSs) in onco-cardiology.

2. New classification in onco-cardiology We divided the field of onco-cardiology into 4 classifications according to each CS.

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D. Sueta et al. / International Journal of Cardiology 220 (2016) 837–841

Fig. 1. The Kumamoto Classification. CS, clinical scenario.

CS1 represents cardiovascular disease associated with malignant disease, also known as “paraneoplastic syndrome.” This classification includes malignant tumors of the heart (metastatic tumor, sarcoma, pericardial mesothelioma, primary lymphoma). A typical case of CS1 is Trousseau's syndrome. In 1865, Armand Trousseau reported an association between cancer and thrombosis (cancer-associated thrombosis) [12], and in 1977, Sack reported that Trousseau's syndrome presented chronic disseminated intravascular coagulation (DIC) associated with non-bacterial thrombotic endocarditis (NBTE) and arterial thrombosis in patients with malignancy [13]. These concepts are reviewed in the literature [14,15]. These thrombosis cases involve tumor-induced vessel compression, such as superior vena cava syndrome, in which the compression is caused by mediastinal tumors. Other cases involve

Fig. 2. Representative Case of Clinical Scenario 1. A large pericardial effusion indicative of carcinomatous pericarditis, as revealed by a cardiac ultrasound.

pulmonary hypertension induced by malignant disease, such as intimal sarcoma of the pulmonary artery (PA) [16,17] and pulmonary tumor thrombotic microangiopathy (PTTM) [18–21]. The former involves the growth of a tumor in the PA intima, which pathologically resembles chronic thromboembolic pulmonary hypertension (CTEPH). The latter is a rare complication of malignant disease (prevalence of 1. 4% in one retrospective autopsy series of patients who died of malignant disease); [18] it is effectively treated by imatinib [22]. Clinically, it is characterized by dyspnea and pulmonary arterial hypertension, which almost invariably progresses to right heart strain and cardiorespiratory arrest within hours to days. Pathologically, widespread small tumor emboli are found [19,20]. CS2 represents cardiotoxicity during the treatment of malignant disease. This type most accurately represents conventional oncocardiology. All anti-neoplastic agents are associated with cardiotoxicity, which can be divided into 5 categories [23]: direct cytotoxic effects of chemotherapy and associated cardiac systolic dysfunction (chemotherapyrelated cardiac dysfunction (CRCD) [24]), cardiac ischemia, arrhythmia, pericarditis, and chemotherapy-induced repolarization abnormalities. CRCD is further divided into 2 subgroups [24,25]: myocardial damage (Type I; anthracycline cardiomyopathy) and myocardial dysfunction [26] (Type II; trastuzumab cardiomyopathy). The dysfunction caused by molecular targeted drugs and novel drugs should also be considered [27]: sunitinib (bevacizumab) cardiomyopathy [28,29] (endothelial dysfunction) induced by anti-angiogenic agents (anti-vascular endothelial growth factor (VEGF) agents); endocrine dysfunction (hyperglycemia, hyperlipidemia) induced by mammalian target of rapamycin (mTOR) inhibitors (everolimus) [30] and tyrosine kinase inhibitors (nilotinib); autoimmune diseases, diabetes mellitus, thyroiditis, myocarditis, and vasculitis induced by programmed cell death protein (PD)1 [31], PD-L1 antibody and cytotoxic T-lymphocyte-associated protein 4 antibody (CTL4A). Furthermore, radiation therapy can also lead to coronary artery disease [32] and fibrotic changes to the valves, pericardium, and myocardium. These examples of cardiotoxicity during treatment have been comprehensively reviewed [33–35]. CS3 represents the concurrence of atherosclerotic disease with malignant disease. This classification includes atherosclerotic disease combined with malignant disease and malignant disease combined


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Fig. 3. Representative Case of Clinical Scenario 2. (A) Bilateral pulmonary emboli of the pulmonary arteries revealed by contrast-enhanced computed tomography. (B) Deep vein thrombosis of the left popliteal vein (red arrow) revealed by contrast-enhanced computed tomography.

with atherosclerotic disease. These concepts have recently been reviewed [8,10]. CS4 represents cardiovascular disease with non-malignant tumor. This classification includes endocrine benign tumors, such as primary aldosteronism, Cushing syndrome and pheochromocytoma [36], as well as non-malignant tumors, such as myxoma. Furthermore, we also propose the concept of oncogenic emergency. We often treat for the cardiovascular diseases in the emergency situation that appears in the cancer progressions and treatments. The representative cases are pericardiocentesis for cardiac tamponade and inferior vena cava filter deployment for deep vein thrombosis (pulmonary embolism). Fig. 1 illustrates the Kumamoto Classification.

effusion (Fig. 2), which was subsequently drained and was found to contain malignant cells. 3.2. CS2 A 40-year-old man with a left testicular tumor was transferred to our department because of a complaint of sudden dyspnea. He had prominent hypoxemia and a high D-dimer concentration. Contrastenhanced computed tomography revealed filling defects in the bilateral pulmonary artery main truncus (Fig. 3A) and the bilateral popliteal veins (Fig. 3B). He was diagnosed with pulmonary embolism, and anti-coagulant therapy was initiated. Because he had been administered alkylating agents (cisplatin) [37], this thrombosis was attributed chemotherapy.

3. Typical clinical scenarios presentation

3.3. CS3

3.1. CS1

A 74-year-old man was transported to our emergency room with severe dyspnea at rest. He was diagnosed with acute decompensated heart failure (Fig. 4A) and admitted to the cardiovascular department. He had a prominent anemia, and gastroscopy revealed a large advanced gastric tumor (Fig. 4B).

After undergoing a bilateral mastectomy for the treatment of breast cancer, a 48-year-old woman visited her primary doctor with general fatigue. On chest X-ray, her heart was enlarged, so she was transferred to our department. A cardiac ultrasound revealed a large pericardial

Fig. 4. Representative Case of Clinical Scenario 3. (A)

Chest X-ray demonstrating acute decompensated heart failure. (B)

A large advanced gastric tumor revealed by gastroscopy.

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The validity of this classification system should be confirmed by future clinical studies. Additionally, this classification system should be further subdivided based on clinical progress. The exploration of future directions, which are illustrated below, is warranted. This classification system should help improve the prognosis of patients with malignant disease. The only limitation of this classification is that there is not enough of a biologic or scientific basis for this new classification. Thus, further pathophysiological and molecular physiological studies, including animal experiments, are warranted. Additional detailed, large-scale clinical studies may be required to verify our theories. Despite this limitation, we have first clearly defined practical onco-cardiology classifications. 5. Future directions

Fig. 5. Representative Case of Clinical Scenario 4 Myxoma of the left atrium revealed by contrast-enhanced computed tomography.

3.4. CS4 A 74-year-old woman was referred to our hospital due to abnormalities on a routine medical screening. Contrast-enhanced computed tomography revealed a 23-mm mass in the left atrium. A cardiac ultrasound revealed a large pericardial effusion (Fig. 5). After tumorectomy, pathological diagnosis revealed that the tumor was a myxoma. 4. Discussion The main conclusions of the present study are as follows: 1) in clinical settings, active malignant disease or a history thereof is often encountered in patients with cardiovascular disease, and it is not uncommon for a patient to struggle with a prior treatment; and 2) we proposed a new onco-cardiology classification, clarifying the concurrence of atherosclerotic disease with malignant disease. Although improvements in molecular targeted therapies, surgical techniques, and radiation therapies have been made, controversies concerning recurrence and adverse effects remain. Many complications of these treatments are observed, and the concurrence of atherosclerotic disease and malignant disease directly impacts prognosis and survival. To achieve successful cardiovascular monitoring and treatment progression and to implement preventive interventions for cardiovascular complications of malignant disease, it is necessary to collect clinical data and perform basic studies on the mechanisms underlying these complications. Cooperation between oncologists and cardiologists in actual clinical situations and among all medical professionals associated with malignant disease care (nurses, pharmacists, and social workers) is mandatory [27], along with cooperation between different institutions. To improve of the prognoses and quality of life of patients with malignant disease, the prevention or early detection of the cardiovascular complications associated with treatment of malignant disease is essential. In this paper, we first defined practical onco-cardiology classifications. These novel and practical recommendations should facilitate mutual understanding and clinical communication between medical providers in actual clinical situations and may be helpful in future works, including prognosis research.

In 2000, MD Anderson had 2 in-house cardiologists and referred most cardiovascular complications to surrounding hospitals at the Texas Medical Center [38]. In 2009, the International Cardioncology Society (ICOS) was established by Dr. Carlo Cipolla at the European Institute of Oncology [39]. The International Conference on Cancer and the Heart has been held every 2 years since 2010 [38]. Future research challenges in onco-cardiology include: ① the comprehensive and long-term follow-up of cardiovascular disease under close cooperation with oncologists, ② a meta-analysis of the risk assessment of cardiac toxicity and the cardiovascular complications of anti-malignancy drugs, ③ the investigation of racial and gender differences in worldwide epidemiological studies, ④ the development of a simple diagnostic marker for patients receiving drug treatment for anti-malignant disease, ⑤ the development of treatments for cardiovascular complications of anti- malignant disease drugs based on their pathogenic mechanisms and ⑥ the education of non-specialists and other medical professionals. Disclosures None. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. Acknowledgments We wish to thank the medical secretaries at Kumamoto University Hospital: Rina Usui, Saki Ogata and Akiyo Kikuchi. We also thank all paramedical staff and clinical secretaries for their support during this study. References [1] D. Sueta, S. Hokimoto, Onco-cardiology: present and future, Int. J. Cardiol. 215 (2016) 38–40. [2] L.M. Brown, C.A. Swanson, G. Gridley, G.M. Swanson, J.B. Schoenberg, R.S. Greenberg, et al., Adenocarcinoma of the esophagus: role of obesity and diet, J. Natl. Cancer Inst. 87 (1995) 104–109. [3] D. Palli, Epidemiology of gastric cancer: an evaluation of available evidence, J. Gastroenterol. 35 (2000). [4] J.H. Cummings, S.A. Bingham, Diet and the prevention of cancer, Br. Med. J. 317 (1998) 1636. [5] D. Sueta, S. Hokimoto, S. Tayama, K. Tsujita, K. Sakamoto, E. Yamamoto, et al., Clinical significance of fecal occult blood screening in patients before percutaneous coronary intervention, Int. J. Cardiol. 182 (2015) 85–87. [6] D. Sueta, S. Hokimoto, H. Ogawa, Could perioperative bleeding complications be predicted using a platelet aggregation test? Thromb. Res. 136 (2015) 491–492. [7] M.C. Whitlock, J. Yeboah, G.L. Burke, H. Chen, H.D. Klepin, W.G. Hundley, Cancer and its association with the development of coronary artery calcification: an assessment from the multi-ethnic study of atherosclerosis, J. Am. Heart Assoc. 4 (2015) e002533.

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