br Mediastinal radiotherapy for Hodgkin s lymphoma is
Mediastinal radiotherapy for Hodgkin's lymphoma is usually given by opposing ap-pa fields. As a consequence, the dose distribution in the heart differs from that in breast cancer patients with a higher expo-sure of the atrio-ventricular annular plane. The excess relative risk of valvular heart disease increased by 2.5% per Gy for doses ≤ 30 Gy, and
disproportionally by 6.5% per Gy, 11.2% per Gy, and 24.3% per Gy for doses between N30–35.9 Gy, 36–40 Gy, and N40 Gy, respectively . More than 70% of patients experienced higher-grade valvular heart dis-ease with progression over time. The median time interval between di-agnosis of Hodgkin's lymphoma and diagnosis of valvular heart disease was 23 years. Systematic cardiovascular screening of childhood cancer survivors after thoracic radiotherapy identified a high number of pa-tients with valvular disease and heart failure not detected prior to screening . The excess relative risk of coronary heart disease has a linear dose-response with a steepness of 7.4% per Gy mean heart dose, similar to breast cancer .
While the use of radiotherapy for childhood cancer is decreasing and total radiation doses and volumes are reduced in Hodgkin's lymphomas , other indications for thoracic radiotherapy such as stereotactic ab-lative radiotherapy for lung cancer and internal mammary node irradi-ation for breast cancer are considered more often. The prognosis of locally advanced lung cancer is improved after definitive radio-chemotherapy, so that cardiovascular late effects become increasingly relevant especially in patients with cardiac risk factors. As the dose dis-tribution in the heart can be estimated before radiotherapy, the individ-ual risk of cardiovascular side effects can be predicted and the surveillance for toxicities tailored accordingly. Awareness of potential cardiovascular side effects led to optimizations of delivered dose distri-butions by better radiation techniques, such as treatment of lung tu-mors with intensity-modulated radiotherapy or of left-sided breast cancer in inspiratory breath-hold .
High dose radiotherapy increases intima-media thickness in large ABTS diammonium salt such as the carotid artery . Increases in carotid intima-media thickness can be detected within 90 days after radiotherapy by ultrasound and represent a risk factor for stroke . Therefore, imaging and surveillance are recommended for early detection of severe stenosis and selection of patients who require treatment.
Endothelial cells are radiosensitive to apoptosis . After brain ra-diotherapy at lower total doses down to 10 Gy with doses b 2 Gy per fraction, diffusion tensor magnetic resonance imaging revealed changes in white matter mean diffusivity and fractional anisotropy parameters related to vascular permeability. Changes increased over time and were detectable after 4–6 months at doses of 30–40 Gy. Diffusion changes in the parahippocampal cingula were found to be related to cognitive decline after radiotherapy . Whole brain radiotherapy can impair cognitive function and does not improve survival when given in combination with stereotactic radiotherapy. Therefore, focal stereotactic radiotherapy alone is recommended for patients with one to three brain metastases .
3.2. Classical chemotherapy
Classical chemotherapy involves a variety of drugs and a broad spec-trum of cardiotoxicity (Supplementary Table 1). Anthracyclines are pro-totypic cardiotoxic agents. Anthracyclines are used in childhood and adult cancers, and their cardiotoxic effects are dose-dependent (Fig. 1): Anthracyclines have multiple cellular and subcellular targets, which contribute to their cardiotoxicity.
A multiple stress theory has been forwarded, which particularly re-fers to the generation of toxic reactive oxygen species (ROS) and the in-hibition of topoisomerase IIβ: Anthracyclines are enzymatically converted in a redox reaction (quinone to semiquinone), and this con-version results in the ROS at multiple cellular locations. Also, anthracyclines react with iron ions, e.g. from heme proteins, to generate ROS . ROS oxidize and thus damage DNA, proteins and lipids . Oxidation of contractile proteins contributes to cardiac contractile dys-function . ROS also stabilize p53, which consecutively initiates se-nescence and apoptotic cell death . One of the major adverse events is the anthracycline-dependent interaction with topoisomerase IIβ, which is required for the repair of ROS-induced DNA damage. Im-paired nuclear transcription reduces the synthesis of contractile
elements and mitochondrial biogenesis (via reduced formation of PGC1α/β) . Topoisomerase Iiβ knockout mice are protected from cardiotoxicity. In mitochondria, anthracyclines through increased ROS formation promote DNA damage and opening of the mitochondrial per-meability transition pore, which, in turn, results in collapse of the mito-chondrial membrane potential, disruption of the outer mitochondrial membrane, release of cytochrome C into the cytosol and the initiation of cell death . Interference of anthracyclines with calcium channels increases intracellular calcium levels and induces calcium overload, which activates various proteases, e.g. calpains to induce cell death through autodigestion and impairs contractile function [47,48]. ROS and calcium act in concert to further promote permeabilization of the mitochondrial outer membrane . In the vasculature, endothelial NO synthase (eNOS) activity is reduced, whereas cytosolic calcium is in-creased in smooth muscle cells , favoring the development of hyper-tension in anthracycline-treated patients and explaining the particular sensitivity of patients with endothelial dysfunction to the development of heart failure . The multiple sites of anthracycline action are reflected in the enhanced susceptibility of specific patients with genetic variants . Given these multiple events, it appears reasonable that anthracycline related cardiotoxicity may occur at early and very late stages during and after therapy. The multitude of deleterious actions also explains the potentially enhanced sensitivity to anthracyclines with pre-existing or intervening cardiovascular pathologies of other or-igin in the sense of a “multiple-stress hypothesis”.