br Spectrum of cancer therapy related
5. Spectrum of cancer therapy-related cardiovascular disease
Therapeutic recommendations are largely derived from AHA/ACC/ ESC cardiovascular guidelines rather than from prospective clinical cardio-oncology trials. Specific cardioprotective approaches to prevent cardiotoxicity in children and adults undergoing cancer treatment are currently tested, including exercise or remote ischemic preconditioning  (e.g. NCT03166813, NCT02471885, NCT01621659, NCT03089502). Currently available data suggest that cardiotoxicity is potentially revers-ible for several therapies [14,15]. Definitions of adverse cardiovascular events from cancer drugs rely on ‘Common Terminology Criteria for Ad-verse Events’ by the National Cancer Institute (CTCAE, ctep.cancer.gov.; Supplementary Table 2). Most patients in cardio-oncology units present with Irinotecan failure but the complete spectrum of cardiotoxicity must be considered .
Hypertension develops in nearly one third of cancer patients, often over the first few weeks of cancer therapy, and may limit prognosis . Established and novel cancer therapies have been associated with increased risk of hypertension (Supplementary Table 1). Hyper-tension develops in nearly one third of cancer patients, often over the first few weeks of cancer therapy, and may limit prognosis . VEGF and proteasome inhibitors pose the highest risks, and this association is probably related to impaired endothelial function, reduced NO forma-tion, and vasoconstriction [66,68]. Post-hoc analyses have even sug-gested the development of hypertension as a pharmacodynamic parameter reflecting effective anti-angiogenic cancer therapy . The diagnosis is based either on office of ambulatory tests, and the severity of hypertension is then graded (Supplementary Table 2). The 2017 AHA guidelines have introduced very strict cut-off values (N120/ 80 mm Hg), while the 2018 ESC guidelines continue to define hyperten-sion with the conventional limits (≥140/90 mm Hg). Patients under VEGF targeted therapies should be particularly monitored during the first cycles, while other therapies may promote hypertension over the entire course of treatment. Upon diagnostic follow-up, hypertension may be caused not only by cancer therapy per se but also by fluid over-load or pain. The current ESC guidelines recommend ACE inhibitors and calcium antagonists as first line option . Many patients will require combination therapies to achieve sufficient blood pressure control. Of note, experimental evidence supports an anti-cancer effect of ACE in-hibitors .
5.2. Venous thromboembolism
Cancer patients are at risk for deep vein thrombosis and pulmonary embolism, and this risk has been related to the tumor itself and to can-cer therapies. Patients with thromboembolic events have a limited prognosis [92,93]. The incidence of thromboembolism depends on the particular malignancy and the therapeutic strategy, but is generally in-creased during the first 6 months of cancer therapy . Many classical and novel therapies have been associated with venous thromboembo-lism . The underlying mechanisms (e.g. reduced endothelial function in drugs targeting VEGF), however, remain incompletely un-derstood. Compression ultrasound and CT are the standard imaging tools for diagnosis. Low molecular weight heparin or unfractionated heparin is given for the prevention of thromboembolism or in established thromboembolic disease according to concurrent guidelines . As long as cancer is active in patients, anticoagulation should be continued. Low molecular weight heparin is preferred for long-term treatment, at least if clinically feasible (e.g. platelet count N 50,000/μl, absence of life-threatening bleeding complications, preserved renal function). Clinical adherence to this recommendation is, however, low. Data on the use of direct oral anticoagulants (DOACs) are limited. Two recent trials testing edoxaban and rivaroxaban in larger cohorts of can-cer patients confirmed their non-inferiority to standard therapy [97,98]. At this point, data for the other two approved DOACs are pending, and a general recommendation for this class of agents can therefore not be given.
5.3. Coronary artery disease
During the course of cancer therapies, patients are at particular risk to develop progression of pre-existing or development of de novo coro-nary artery disease. Coronary artery disease manifests itself as stable an-gina or acute coronary syndrome albeit with arterial thrombus formation during active cancer therapy or even years thereafter. This also applies to the development of acute cerebrovascular events . Pa-tients with cancers associated with smoking (e.g. lung cancer, bladder cancer, head and neck cancers) have more frequently also coronary ar-tery disease. Careful evaluation of the patient's individual and family