- Academic Editor
Radiotherapy (RT) is a mainstay of Breast Cancer (BC) patients therapy. Nonetheless, unintended irradiation of the heart and its substructures can result in cardiac toxicity, jeopardizing long-term survivors’ quality of life (QOL). Advances in RT delivery techniques deeply impacted this clinical scenario. Indeed, given the non-negligible burden of cardiotoxicity, modern cardiac sparing approaches have a pivotal role. Nonetheless, further evidence is eagerly awaited regarding patients’ selection, clinical predictors, biological markers, and particularly heart substructures dose-constraints.
A crucial goal for modern cancer care is maintaining the balance between achieving optimal disease control and minimizing the risk of late-induced sequelae, particularly in patients with more prolonged expected survival. In terms of radiotherapy (RT), thoracic cancers can be particularly challenging due to the presence of “critical” organs at risk (OARs), namely the heart and lungs. Breast cancer (BC) is the first female cancer worldwide [1]. In Italy, about 55,000 new cases of BC were diagnosed in 2020 [2]. Postoperative RT is a mainstay of BC treatment, drastically impacting disease control and leading to survival benefits [3, 4, 5, 6].
Nonetheless, unintended irradiation of the heart and its substructures can result in cardiac toxicity, jeopardizing survivors’ quality of life (QOL) [3, 4, 7, 8]. Indeed, although patients identify the cure as their most important treatment outcome, late complications related to treatment are a recognized problem as follow-up increases among those cured within this oncologic setting.
All cancer treatment modalities are associated with long-term morbidities, magnified in long-term survivors [9]. In terms of cardiac toxicity, anthracycline-based chemotherapy (ChT) regimens are associated with a risk of ventricular or coronary artery alterations, increasing when RT doses to large heart volumes are involved [10]. Radiation-induced heart diseases (RIHD) have several pathogenic pathways, such as microvascular injury, myocardial remodeling, oxidative stress, inflammation, fibrosis, and apoptosis, contributing to: vessels micro- and macroangiopathy leading to coronary artery disease (CAD), damage of the atrioventricular node/conduction system, accelerated atherosclerosis, and myocardial fibrosis [11, 12, 13, 14]. These pathways and the corresponding clinical implications are under the research spotlight [15, 16]. Indeed, long-term radiation-related cardiac toxicity can be seen as arrhythmias, pericarditis, congestive or ischemic heart disease, and valvular damage [17].
The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis,
comparing surgery plus RT versus surgery alone in BC patients, showed an increase
of 27% in mortality from cardiac events, mainly caused by coronary artery
disease [3]. Moreover, the 15-year follow-up update of the EBCTCG confirmed a
correlation between the mortality related to cardiac disease and the doses to the
heart [4]. There is evidence that this correlation is stronger in trials
reporting larger mean cardiac doses and that the risk of death from heart disease
increases by 3% per Gy (p
Overall, BC patients receiving incidental cardiac radiation have been estimated
to have a relative risk of developing cardiac events between 1.2 and 3.5 in a
15-year follow-up period, compared with patients that did not receive RT
[3, 7, 19, 20, 21]. A dose
Furthermore, left-sided breast RT and chest-wall irradiation have been associated with more significant mortality in patients developing cardiac toxicity after a decade from treatment [27, 28, 29].
A cohort study by van den Bogaard et al. [30] included 910 consecutive female patients with BC treated with postoperative RT. The primary end point was cumulative incidence of acute coronary events (ACEs) within 9 years of follow-up. The median MHD was 2.37 Gy. The cumulative incidence of ACEs increased by 16.5% per Gy (p = 0.042). The volume of the left ventricle receiving 5 Gy (LV-V5) was the main prognostic dose-volume metric [30].
The Breast Cancer and Cardiotoxicity Induced by Radiotherapy (BACCARAT)
prospective study consisted of left or right unilateral BC patients treated with
3D-Conformal RT (3D-CRT) between 2015 and 2017 [31]. Dose distributions were
generated for 89 left-sided BC patients (MHD = 2.9
Indeed, assessing the substructures doses is the key to reduce the risk of cardiac complications [23]. Moreover, coronaries motion and the use of compensatory expansion margins should be taken into account [32].
Thus, modern cardiac avoidance approaches during BC irradiation have become a significant matter of interest due to the potential benefit of decreasing cardiac toxicity and its related clinical manifestations, particularly for left-sided disease [3, 7].
Over the last decades, a significant contribution to minimizing the dose to the heart during BC irradiation and, subsequently, to potentially reduce the risk of radiation-induced cardiovascular events has been reached thanks to the development of modern RT techniques.
Intensity-modulated RT (IMRT) and volumetric arc therapy (VMAT) have been increasingly adopted in breast RT, especially for left-sided presentations [33, 34, 35]. Compared to 3D-CRT, intensity-modulated techniques can improve cardiac dosimetry [36, 37, 38, 39].
Before generating treatment plans, particularly for left-sided and young BC patients, an accurate choice of the plan technique should be made [40].
Modern RT may also be combined with breathing-adapted approaches to achieve significant reduction in the heart dose [41, 42].
The breath-hold approach is one of the most well-investigated cardiac-avoidance strategies. Indeed, inspiration breath-hold gives the best cardiac dislocation since the heart moves away from the chest wall, decreasing the heart volumes exposed to irradiation [43, 44, 45, 46]. Moreover, such an approach may allow for expansion margins reduction, resulting in OARs’ major protection [47]. Deep inspiration breath hold (DIBH) has several technical options [48, 49, 50, 51, 52, 53, 54, 55, 56].
Sakka et al. [35] reported a significant reduction in the dose to the heart and the LAD-CA observed with DIBH compared to free-breathing (FB) by increasing the heart-to-chest wall distance in both IMRT and VMAT plans.
Korreman et al. [57] showed a drastic reduction in the heart V50 and
the median LAD-CA volume for DIBH in left-sided presentations. An extensive
systematic meta-analysis comparing DIBH and FB in a large left-sided BC patients
cohort showed a significant DIBH dosimetric benefit regarding both the heart and
LAD-CA (p
Noteworthy, the role of partial breast (PB) irradiation as a cardiac sparing approach has also been evaluated.
Compared to the whole breast irradiation (WBI), accelerated partial breast irradiation (APBI) can decrease the heart and surrounding OARs exposure [60, 61, 62, 63, 64]. However, few studies compared APBI and WBI or focused on cardiovascular toxicity [62, 63, 64].
Chiang et al. [64] recently conducted a planning comparison study
comparing the critical OARs dosimetry among PB irradiation, including both
Interstitial Brachytherapy (ISBT) and external beam radiotherapy (PB-EBRT), and
WBI in 12 left-sided BC patients. The MHDs in both APBI techniques were all
significantly lower compared to the WBI technique (p
Finally, proton therapy (PT) has to be taken into account when mentioning modern RT approaches. Given unique ballistic properties, extreme OARs avoidance can be reached when treating the thoracic district with PT [17].
Fagundes et al. [65] compared PT with 3D-CRT, helical tomotherapy, and
VMAT in 10 patients with stage III left-sided BC. The MHD was significantly
(p
In a systematic review of published clinical data, Kammerer et al. [66] highlighted that PT often decreases the MHD by a factor of 2 or 3, i.e., 1 Gy with PT versus 3 Gy with 3D-CRT and 6 Gy for IMRT [66].
Nevertheless, PT uncertainties have to be considered [17, 67], including mainly the RBE changes along the beam path and uncertainties due to tissue density variations/organ motion [67]. Thereafter, coronary arteries certainly represent the structures at the highest risk in this context [67].
Cardiotoxicity can unfavorably counterbalance the oncological benefits of RT. Modern RT, based on upgraded delivery techniques, positively impacts such adverse events risk reduction. Indeed, given the non-negligible burden of cardiotoxicity in long-term survivors, modern cardiac sparing techniques have a pivotal role in this clinical scenario. Nonetheless, further evidence is awaited regarding patients’ selection, clinical predictors, biological markers, and heart substructures dose-constraints.
GCI and VC gave the idea and wrote the main manuscript text. GCI, VC and UR decided the method of the literature review. GCI, VC and UR reviewed references. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work to take public responsibility for appropriate portions of the content and agreed to be accountable for all aspects of the work in ensuring that questions related to its accuracy or integrity.
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This research received no external funding.
The authors declare no conflict of interest. Giuseppe Carlo Iorio is serving as one of the Guest editors of this journal. We declare that Giuseppe Carlo Iorio had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Felix Wong.
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