br Cardiovascular disease particularly previous
Cardiovascular disease (particularly previous myocardial infarction and valvular disease) greatly increases the risk for toxicities, particularly in patients receiving anthracycline-based chemotherapies [16–18]. The relation of risk factors to side effects from the novel therapies (molecu-larly targeted inhibitors or immune therapies released over the past years) is of growing concern . Whenever feasible, a detailed assess-ment of the patient's history prior to administration of cardiotoxic agents is recommended. This consideration should be directed at any signs of angina, exertional dyspnea, syncope, palpitations, claudication and edema. An electrocardiogram (ECG) is mandatory in patients re-ceiving chemotherapy (e.g. for concurrent arrhythmias and/or as base-line reference in case of cardiovascular events under therapy). The benefit from assessment of biomarkers before chemotherapy is unclear. In an unselected cohort, elevated troponin levels prior to administration of a cardiotoxic drug predicted mortality during follow-up . Bio-markers are recommended by current AHA/ESC guidelines for the de-tection of significant cardiovascular pathologies. Overt cardiovascular disease is treated according to current guidelines. However, the need for rapid initiation of cancer therapy in symptomatic patients or patients with high tumor load may require individual decisions, including the treatment of three-vessel coronary artery disease, aortic stenosis or mi-tral valve regurgitation by catheter-based approaches rather than sur-gery in younger patients. Such approach avoids delay from surgery and subsequent recovery before cancer therapy. Another important issue is to minimize the use of cardiovascular interventions and devices requiring highly intensive and prolonged anticoagulation/anti-platelet medication, which can greatly increase the risk of hematotoxic cancer
therapies and/or interventions (e.g. mechanical heart valves). Multidis-ciplinary discussion between the treating oncologist and cardiologist and with the surgery team is mandatory.
3. Cardiotoxicity of selected/clinically relevant cancer therapies
The cardiotoxicity of cytotoxic agents e.g. anthracyclines or high doses of alkylating agents, and radiation fields involving thorax, AzBTS-(NH4)2 and critical vascular structures has long been appreciated [3,14,15]. However, the adverse effects of novel treatments, such as protein kinase inhibitors and immune checkpoint inhibitors (ICI, Supplementary Table 1), and algorithms for their optimal management remain an area of study.
With the favorable development of long-term survival in certain cancers the toxic effects of chest irradiation have become appreciated. The relative contribution of radiation vs. chemotherapy can often only be estimated. Radiotherapy is used in about 35% of cancer patients within one year of diagnosis, provided that there is an adequate infra-structure . Pericarditis can occur early after high dose radiotherapy and has long been the only quantitatively considered radiotoxicity to the heart, with a risk of 5% at 5 years after doses of 40 Gy to the whole organ with conventional fractionation . Pericarditis may present in its effusive or constrictive form, and the latter is difficult to diagnose . Acute pericarditis has become rare due to advances in radiation techniques and is characterized by massive immune infiltration and ex-udation. Chronic pericarditis, however, is one of the most frequent radiation-induced cardiotoxicities and also occurs following low-dose radiation . Twenty percent of patients with chronic pericarditis de-velop clinical signs of constriction. The diagnostic workup includes echocardiography and invasive hemodynamics , and complete sur-gical pericardiectomy remains the definite therapy. Radiation dose limits for pericarditis were employed in contemporary trials on defini-tive radio-chemotherapy for lung cancer . With the advent of 3D conformal treatment planning in radiotherapy, dose distributions within the heart are calculated before radiotherapy . Meanwhile, long-term follow-up of larger cohorts of patients with tumors of good prognosis, particularly breast cancer and Hodgkin's lymphoma, are available. Dose-dependent adverse effects of radiotherapy on the heart manifest as ischemic heart disease , valvular heart disease, cardio-myopathy and congestive heart failure .
Ischemic heart disease is the most common adverse cardiovascular event after radiotherapy for breast cancer . Ionizing radiation expo-sure of the heart increases the individual patient's base line risk of ische-mic heart disease by 7.4% per Gy mean heart dose, and this excess relative risk remains rather constant during follow-up until 20 years after radiotherapy. Comorbid patients with preexisting cardiac risk fac-tors have a larger absolute excess risk of ischemic heart disease than pa-tients without risk factors after the same radiation exposure. The ‘Early Breast Cancer Trialists' Collaborative Group’ analyzed the risk of heart disease in N40,000 women from 75 trials randomized to breast cancer radiotherapy vs. no radiotherapy  and found an increase in the rel-ative risk of cardiac mortality of 4.1% per Gy mean heart dose . The most common cause of radiation-dependent cardiac mortality in this analysis was ischemic heart disease followed by heart failure and valvu-lar disease. Comparing toxicities in patients who receive tangential field radiotherapy for left-sided versus right-sided breast cancer, an in-creased risk of cardiac mortality was found in patients treated with left-sided radiotherapy .