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Review

Current Cardioprotective Strategies for the Prevention of Radiation-Induced Cardiotoxicity in Left-Sided Breast Cancer Patients

by
Vasiliki Nikovia
1,†,
Evangelos Chinis
1,†,
Areti Gkantaifi
2,
Maria Marketou
3,
Michalis Mazonakis
4,*,
Nikolaos Charalampakis
5,
Dimitrios Mavroudis
6,
Kornilia Vasiliki Orfanidou
1,
Antonios Varveris
7,
Chrysostomos Antoniadis
7 and
Maria Tolia
7
1
Medical School, University of Crete, Vassilika, 71110 Heraklion, Greece
2
Radiotherapy Department, Theagenio Anticancer Hospital of Thessaloniki, 54639 Thessaloniki, Greece
3
Cardiology Department, University General Hospital of Heraklion, Heraklion, 71110 Heraklion, Greece
4
Department of Medical Physics, Faculty of Medicine, University of Cret, Iraklion, P.O. Box 2208, 71003 Heraklion, Greece
5
Oncology Clinic, Metaxa Cancer Hospital, Mpotasi 51, 18537 Piraeus, Greece
6
Department of Medical Oncology, University General Hospital of Heraklion, 71500 Heraklion, Greece
7
Department of Radiotherapy, University Hospital/Medical School, University of Crete, Vassilika, 71110 Heraklion, Greece
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
J. Pers. Med. 2023, 13(7), 1038; https://doi.org/10.3390/jpm13071038
Submission received: 27 March 2023 / Revised: 11 May 2023 / Accepted: 20 June 2023 / Published: 24 June 2023
(This article belongs to the Section Personalized Therapy and Drug Delivery)
Review Reports Versions Notes

Abstract

:
Background: Breast cancer (BC) is the most common malignancy in females, accounting for the majority of cancer-related deaths worldwide. There is well-established understanding about the effective role of radiotherapy (RT) in BC therapeutic strategies, offering a better local–regional control, prolonged survival, and improved quality of life for patients. However, it has been proven that conventional RT modalities, especially in left-sided BC cases, are unable to avoid the administration of high RT doses to the heart, thus resulting in cardiotoxicity and promoting long-term cardiovascular diseases (CVD). Recent radiotherapeutic techniques, characterized by dosimetric dose restrictions, target volume revision/modifications, an increased awareness of risk factors, and consistent follow-ups, have created an advantageous context for a significant decrease inpost-RT CVD incidence. Aim: This review presents the fundamental role of current cardioprotective strategies in the prevention of cardiotoxic effects in left-BCRT. Material and Methods: A literature search was conducted up to January 2023 using the Cochrane Central Register of Controlled Trials and PubMed Central databases. Our review refers to new radiotherapeutic techniques carried out on patients after BC surgery. Specifically, a dose evaluation of the heart and left anterior descending coronary artery (LADCA) was pointed out for all the included studies, depending on the implemented RT modality, bed positioning, and internal mammary lymph nodes radiation. Results: Several studies reporting improved heart sparing with new RT techniques in BC patients were searched. In addition to the RT modality, which definitely determines the feasibility of achieving lower doses for the organs at risk (OARs), better target coverage, dose conformity and homogeneity, and the patient’s position, characteristics, and anatomy may also affect the evaluated RT dose to the whole heart and its substructures. Conclusions: Modern BC RT techniques seem to enable the administration of lower doses to the OARs without compromising on the target coverage. The analysis of several anatomical parameters and the assessment of cardiac biomarkers potentiate the protective effect of these new irradiation modalities, providing a holistic approach to the radiation-associated risks of cardiac disease for BC patients. Despite technological advances, an inevitable cardiac radiation risk still exists, while adverse cardiac events may be observed even many years after RT. Studies with longer follow-ups are required in order to determine the effectiveness of modern breast RT techniques.

1. Introduction

Breast cancer (BC) constitutes the leading female malignancy (2.3 million diagnosed cases every year) and most common cancer-related death in women worldwide [1]. In total, 19.6 million disability-adjusted life years (DALYs) out of 107.8 million DALYs deriving from female malignant neoplasms are globally attributed to BC [2].Improved survival and clinical outcomes have been demonstrated in recent decades [3], owing to more advanced screening methods/earlier diagnoses, improved available tools, and the comprehensible awareness-raising of related risk factors.
The majority of BCs are unilateral [4], with a slightly higher prevalence of left-sided BC but no significant evidence on the specific causes of BC laterality [5].However, several studied factors could be responsible for this observed laterality, such as breast-feeding patterns, a pattern of cerebral asymmetry, handedness, breast size and density, the impact of hormonal fluctuation on the mammary glands, genetic predisposition, and sleeping habits, etc. [6]. A well-emphasized factor involved inunilateral cancer cases is alack of stability during breast development or alaterality, namely a fluctuating asymmetry between the left and right breast [4].
RT is indicated for the majority of BC-conserving surgery cases, enhancing long-term survival rates [7,8,9,10]. Left-sided BC patients, who receive neoadjuvant [11] or adjuvant RT, may present a higher risk of CVD development [12,13,14].Left-sided BCs present metastases to the regional lymph nodes less commonly than right-sided cancers [5] and require the delivery of a more extended RT field. Left-sided BC is related to worse clinical outcomes and higher death rates than right-sided BC [15]. RT may induce damage to the endothelial cells’ microvascular environment, activating the inflammatory cascade of atherothrombosis, with a subsequent occlusion of blood flow, ischemia or infarction, myocardial cell death, and fibrosis [16]. At the same time, it provokes inflammation, oxidative stress, the thickening and fibrosis of vessels media adventitia, and consequential atherosclerosis in the large vessels such as the coronary and carotid arteries.
The main clinical manifestations of RT-induced cardiotoxicity include pericarditis, myocarditis, arrhythmia, coronary artery disease, myocardial infarction, congestive heart failure, valvular heart disease, and cardiomyopathy [11]. The risk of cardiotoxicity and CVD-induced mortality may be even higher when specific risk factors coexist. Emphasis should be given to the treatment of cardiovascular risk factors that increase cardiac side effects, such as diabetes mellitus, arterial hypertension, dyslipidemia, obesity, age, smoking, a sedentary lifestyle, and unhealthy nutrition, and to the control of underlying cardiovascular diseases [17].
Obesity, dyslipidemia, excessive alcohol consumption, tobacco use, hormone replacement therapy, insufficient physical exercise, the consumption of processed food, and psychological stress are classified as modifiable risk factors, and age (over 40), gender (female), race, genetic profile, a family history of BC, previous breast diseases, age at menarche, number of pregnancies and births, breast density, and previous radiation exposure as non-modifiable factors [13,18,19,20,21]. However, even with anelimination of all the modifiable factors, the maximum risk decrease achieved would be approximately 30% [2].
The great number of cardiac death sattributed to RT’s late cardiotoxic effects, observed after a long-term follow-up, necessitates the development of optimal RT methods, providing safety and a better quality of life for patients [22,23]. The concept of personalized medicine refers to the tailoring of irradiation to each left-sided BC patient’s unique characteristics. Therefore, the aim of the present review is to highlight the availability of current cardioprotective strategies concerning their potential heart-sparing benefit.

2. Materials and Methods

We included all papers offering any data concerning new radiotherapeutic techniques with dosimetric dose restrictions to the heart and LADCA carried out on patients after BC surgery. Electronic databases were searched using synonyms for “left breast cancer”, “radiotherapy”, “irradiation”, “cardiotoxicity”, and “radiation-induced cardiotoxicity” in women with BC. A filter was not used, since any type of study was considered, without a restriction to randomized controlled trials. PubMed and the Cochrane Database of Controlled Trials were searched up until January 2023 with a restriction to English-written publications. The articles were procured for a meticulous inspection and evaluation of their contiguity. Cross references from the included studies were hand searched. All the titles and abstracts retrieved were printed and reviewed manually and independently by two reviewers. The studies that clearly did not meet the inclusion criteria were excluded. Finally, original articles, literature reviews, trials, and meta-analyses were included in our review.

3. Results

We identified the studies reporting on the availability of current cardioprotective strategies that could be applied to newly diagnosed left-sided BC patients for the prevention of radiation-induced cardiotoxicity. We searched only in PubMED/Central. In addition to the optimal RT method, which definitely determines the feasibility of achieving lower doses for the organs at risk (OARs), the patient’s position, parameters, and anatomy may also affect the evaluated RT dose to the whole heart and its substructures. Detailed data of the included studies are summarized in Table 1 and Table 2.

4. Discussion

Although a great number of studies have extensively analyzed late cardiotoxicity after left-breast RT, the data about early subclinical cardiac changes remain scarce [32]. Characteristically, in 2019, Gkantaifi et al. clearly illustrated how important the introduction of new tools is for the detection of early cardiotoxicity in left-BC patients after RT [33]. There is a definite need to focus on the roles of strain echocardiographic imaging and specific cardiac biomarkers concerning their potential to predictearly cardiac dysfunction, thus leading to an earlier detection of patients at risk, better clinical outcomes, and an improved quality of life. To be more specific, strain echocardiographic imaging has been found to be a sensitive tool for predicting early cardiac damage after chemotherapy, as well as in various conditions [34,35,36,37]. However, its role in detecting early cardiotoxicity after breast RT is still questionable, with reported decreased levels of strain parameters from a few weeks to 2 years after RT [38,39]. Thus, these changes might predict early cardiac abnormalities, demonstrating the usefulness of strain rate imaging. Furthermore, measuring specific biomarkers in BC patients’ serum during or after RT could contribute to the prediction, diagnosis, and risk assessment of cardiovascular disease [40].Studies have shown that the appropriate biomarkers in patients undergoing RT include cardiac troponin T (cTnT), cardiac troponin I, and natriuretic peptides such as B-type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (NT-proBNP) (cTnI). Elevated levels of these molecules may indicate increased myocardial stretch and thus may be used as biomarkers for left ventricular dysfunction and heart failure [41,42]. Although such biomarkers are insufficient on their own to determine the path of treatment for each patient, they should be used as a trigger or follow-up tool for the attending physician [43].

5. Relevant Sections

5.1. Natural Antioxidants

Natural products have also attracted much scientific interest for their potential impact on the prevention of radiation side effects, thus reducing the risk of heart tissue damage. Indeed, the pathophysiology of oxidative stress and the production of free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), possess major roles in RT-induced cardiovascular disease [44,45]. Free radicals react with cell macromolecules, leading to DNA and protein oxidation and lipid peroxidation, provoking irreversible damage to cells and disrupting normal cells or tissue function and homeostasis. Thus, the development and use of agents that could eliminate these free radicals or limit their activity would prevent and repair the irradiation side effects, reducing the risk of heart tissue injury. Studies have illustrated some natural antioxidants that may inhibit the free radicals’ damage and reduce the incidence of heart disease, such as:
  • Vitamin E: reduces nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, inhibits lipid peroxidation, and downregulates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB).
  • Silymarin: stimulates nuclear factor erythroid 2–related factor 2(Nrf2) expression and downregulates NF-κB.
  • Resveratrol: reduces NADPH oxidase uncoupling and endothelial nitric oxide (eNOS) and upregulates antioxidant defense enzymes.
  • Lycopene: scavenges singlet oxygen, sulfur, nitrogen dioxide, and sulfonyl-free radicals.
  • Melatonin: stimulates the enzymatic antioxidant system.
  • Hesperidin: passivates NADPH oxidase and inhibits Transforming growth factor beta 1 (TGF-β1) mRNA expression.
  • Curcumin: (a) attenuates the IL-4 protein upregulation and its receptor, IL4Ra1, and (b) the expression of the dual oxidases (Duox1 and Duox2) responsible for extracellular matrix stabilization via oxidative cross-linking.
  • Zingerone: (a) decreases malondialdehyde levels, (b) increases glutathione/catalase activity, (c) reduces inflammatory markers, i.e., tumor necrosis factor-alpha, cardiac myeloperoxidase activity, and cyclooxygenase-2 protein, and (d) reduces caspase-3 gene expression and nuclear DNA fragmentation.
  • Caffeic acid phenethyl ester (CAPE): reduces the activities of (a) malondialdehyde (MDA), (b) xanthine oxidase (XO), and (c) adenosine deaminase (ADA), and increases the levels of (d) nitrate/nitrite (NO(x) and (e) superoxide dismutase SOD in heart tissue [45,46].

5.2. Pharmacological Drugs

Furthermore, the development of pharmacological drugs represents another emerging option for the prevention of late cardiotoxicity. Even though limited research has proven their benefit, studies have revealed that the administration of metformin can be cardioprotective in left-sided BC patients who undergo adjuvant RT [46,47,48,49]. Characteristically, metformin has a great number of actions related to endothelium function, such as antifibrotic effects, impeding the formation of the inflammatory environment and oxidative stress in endothelial cells, the promotion of endothelial cell proliferation and differentiation, vascular tone regulation, and the arrest of endothelial to mesenchymal transition. Studies have suggested the administration of metformin for left-sided BC and declared that biguanide not only prevents RICT toxicity, but the probability of coronary artery disease can also be significantly reduced [25,50,51,52,53]. Yu JM et al. [49], in a retrospective national cohort study, prescribed metformin for >28 days (defined daily dose) to2.062 early-stage left-sided BC patients. The authors found that metformin use during adjuvant breast irradiation significantly reduced the risk of major heart events (adjusted hazard ratio [aHR], 0.789; 95% confidence interval [CI], 0.645–0.965; p = 0.021).

5.3. Modern Radiotherapy Techniques

Before the widespread use of three-dimensional conformal RT (3DCRT), heart irradiation was inevitable [54,55]. Characteristically, the anterior, anteroseptal, and anterolateral left ventricular walls, and even more, their apical parts and the LADCA, were exposed to higher radiation doses in left-sided BC cases [26,56,57]. RT for left BC may involve some incidental heart exposure to ionizing radiation. Modern RT methods can drastically reduce the effect of this exposure on the subsequent risk of heart disease [58]. In order to minimize adverse cardiac toxicity, a remarkable effort has been made to develop new RT techniques, so as to achieve reduced heart irradiation without simultaneously compromising the target coverage.
Research has revealed an association between left ventricular function and RT dose and a linear relationship between coronary artery disease and radiation dose to cardiac tissue, as well as an association between myocardial infarction or ischemic heart disease and mean heart dose (MHD) [59]. Darby et al. demonstrated that the CVD risk increased linearly with the MHD. The risk was 7.4% per gray, with no clear threshold below which there was no risk. The risk started within the first 5 years after irradiation and continued for at least 20 years. Ref. [18] while a few years later, Skytta and colleagues reported increased serum Troponin T levels with reported MHD 4Gy [60].Additionally, in a recent small prospective study, Gkantaifi et al. highlighted the need for assessment in RT treatment planning, additionally to whole heart volume, as well as dose constraints for cardiac substructures—such as the left anterior descending artery (LAD) and left ventricle (LV)—for patient’s improved heart protection [61]. Actually, although the radiation exposure to the whole heart and left ventricle was low in the whole study, there was a reported higher exposure to the LAD, raising major concerns about the vulnerability of the latter structure.
However, there has not yet been determined a threshold above which a significant risk of cardiac toxicity may occur; therefore, an increased need for continual dose fluctuation is still observed. In this context, the majority of new RT methods and revised treatment planning protocols focus on are duction in their radiation of OARs and consequently in radiation-induced cardiotoxicity (RICT) [62]. Except for classic free breath 3D conformal RT, the new radiotherapeutic methods that will be further developed below include prone positioning, respiratory-gating and breath-hold RT, deep-inspiration breath hold (DIBH) and gating, forward-planned and inverse-planned intensity modulated RT (IMRT), volumetric-modulated arc therapy (VMAT), helical tomotherapy, and proton therapy [53].

5.3.1. Prone Positioning

Research supports that a prone set-up may reduce heart irradiation, as it allows for the breast to fall from the chest wall while it is restrained by the bed, increasing, in this way, the distance between the heart and irradiated breast tissue [63]. The ability of a meticulously planned prone RT is of vital significance, so as to minimize the treatment fields without penetrating the heart orjeopardizing the target coverage. Previous studies have reported that the benefit of prone positioning during BC RT was controversial due to the anterior translocation of the heart, indicating that only the ipsilateral lung may benefit from it [64,65,66]. Other studies have demonstrated that mainly women with large-sized breasts would profit from this method, not only because their breast would be compressed in the supine set-up and not homogenously irradiated, but compared to small-sized breast patients, the distance between the OARS and breast would be greater. Characteristically, in 2014, Varga Z et al. [65] included 83 left BC patients in their study comparing RT plans in both prone and supine positions, aiming to indicate the optimal tool for the ideal treatment position for BC patients. Actually, many patients presented a high exposure to the heart and LAD in the prone position, illustrating the significant role of patient’s anatomy, BMI, and breast size [34]. Nevertheless, recent studies have suggested that prone RT predicts less long-term cardiotoxicity, independently of a patient’s breast size, in comparisonto the supine set-up, with both the heart and ipsilateral lung receiving lower doses [67,68].

5.3.2. Respiratory Gating Techniques

Respiratory gating (RG) techniques, including deep inspiration breath hold (DIBH), have been widely used during the last few years for postoperative left-sided BC RT, as more studies have increasingly proven reduced heart irradiation and a consequently reduced risk for RT-induced cardiac disease with these methods [56,62]. The two most commonly used DIBH techniques include voluntary DIBH (vDIBH) and involuntary or moderate DIBH (iDIBH). iDIBH requires active breathing control (ABC) devices, which control airflow and halt it over specific volumes [69]. In contrast, vDIBH is based on patient guidance, in order to monitor their respiratory cycle. During the treatment and delivery of radiation, patients are trained to inhale deep and hold their breath for a specific period of time. The aim of administering radiation during a deep breath is to ensure that it occurs when the distance between the breast and chest wall is at a maximum level during the breath cycle, as the heart moves posteriorly and inferiorly, being influenced by diaphragm flattening and lung expansion [70,71]. DIBH can reduce high-dose areas and the mean heart dose by 33–66% from the initial RT dose, also providing an improvement in LADCA and lung dose. In a recent study by Tang L et al., including 11 left BC patients undergoing CT either in free breathing or DIBH, a significantly reduced dose to the heart and LADCA was found with DIBH. Furthermore, compared to 3DCRT plans, VMAT achieved a significant dose reduction [27]. In 2021, Ferdinard et al. conducted a prospective studywith31 left BC patients, indicating a significantly reduced dose to the heart and LAD with the DIBH technique compared to free breathing (MHD 2.4 Gy vs. 4.01 Gy) [24]. Moreover, Sakyanun P et al. and Ferini G et al. illustrated a decreased radiation exposure to the heart and LAD by applying the DIBH technique compared to free breathing in left BC patients. The maximum heart distance and breast size were found to influence the MHD [16,72]. Apart from the foregoing, Darby et al. indicated that the incidence of major coronary events is increased by 7.4%for each 1Gy in MHD, with no determined threshold [18]. On the contrary, Taylor et al. showed a 4% increase in CVD mortality per Gy MHD, defining the dose of 4 Gy as the threshold, below which there is no extra risk of CVD mortality [73]. Although DIBH is the most frequently applied cardio sparing RT technique, many physicians and institutions mention that an increased treatment time is required, consequently inducing an additional workload [71]. As a result, meticulous patient selection is necessary and should be based on maximum heart distance, parasagittal cardiac contact distance, tumor characteristics, a patient’s anatomical features, the technique convenience, patient compliance, accurate training, and tolerance [74]. Currently, a great number of studies have concluded that DIBH is superior to Free Breathing RT regarding simultaneous cardioprotection and target coverage [59,62].Thus, many researchers have suggested that the delivery of the DIBH technique constitutes a more effective heart-sparing method for left-sided BC cases [24,74,75]. In a recent retrospective study from Ngujen et al., a reduced heart dose with the DIBH technique was demonstrated, even in cases of internal mammary nodes irradiation (−56.4%) [31]. During DIBH, both in simulation and an RT course, the patient takes a deep breath for a period of time. An appropriate inspiration and chest excursion allow for lung expansion and diaphragm flattening. DIBH takes the advantage of a more favorable heart position anatomy, displacing the heart from the tangential radiation fields.
Regarding the method of breath adapting RT (BART), enhanced inspiration gating (EIG) is also included. During EIG, patients are audio-coached throughout the entire training session (including CT scanning, set-up imaging, and RT course). The patient breathes deeper than normal, but unlike for DIBH, the patient does not perform normal breathing between the deep breaths. A real-time positioning management system (marker block with six reflective markers placed on the chest of the patient, and infrared light reflected by these markers that is detected by a camera to monitor the antero-posterior chest movement) is used to monitor the patients’ breathing. The patients are instructed to take a deep breath, adjusting separately the duration of inspiration and expiration. This RT technique administers lower radiation doses to the OARs in comparison to the Free Breathing technique, reducing the risk of long-term cardiovascular effects. Although some studies have proven that both RG techniques offer similar cardioprotective action and do not compromise the target coverage, others have indicated that DIBH achieves greater reductions in the MHD and LADCA dose [33,62]. Actually, the retrospective study from Edvardsson et al., regarding 32 patients undergoing tangential or locoregional adjuvant breast free-breathing RT, reported a decreased median V25Gy for the heart and LAD by applying enhanced inspiration gating, from 2.2% to 0.2% and 40.2% to 0.1% (p < 0.001), respectively [25].

5.3.3. Proton Beam Therapy

Proton Beam Therapy (PBT) has been used in clinical medicine since the mid 1980s, but not to a large extent; therefore, it poses limitations such as the cost of treatment facilities, as well as dose and range uncertainties due to radiation’s sensitivity to the density of the substances it crosses [76,77]. Proton RT is a rapidly evolving irradiation modality because of its energy deposition according to Bragg Peaks, which means reduced entrance and exit doses and the administration of peak energy to the target volume, in an overall more advantageous dose-depth distribution [78]. As a consequence, PBT can be selectively applied to patients with left-sided BC in order to avoid heart exposure to irradiation. In 2018, the study results from Luo L et al. about postmastectomy RT with protons reported promising conclusions on local control and toxicity in a 3-year follow-up [30].
A major PBT constriction is the high cost and big size of the gantry, impeding its widespread use and availability. Fixed proton beamlines (FBLs) aim to overcome this obstacle by permitting the implementation of proton RT in conventional treatment rooms, which is not an easily available approach. There is limited evidence proving PBT’s advantages over other heart-sparing radiation techniques, so further research is required for proton RT application in patients achieving maximum benefits.

5.3.4. Intensity Modulated Radiotherapy

Intensity Modulated RT (IMRT) represents an advanced form of 3D-Conformal RT that alters the intensity of multiple photon beams and delivers them from diverse directions, creating highly conformal dose distributions [33,79]. With regard to the literature, IMRT achieves the administration of lower doses to a greater proportion of cardiac tissue, thus resulting in an improved sparing of the OARs, dose uniformity, and the coverage of the target volume in comparison to3D-CRT [80].Studies have illustrated that the irradiation of the internal mammary chain (IMC) in left-sided BC patients increases the cardiac dose [81].
Treatment with IMRT is particularly beneficial for node-positive BC patients, as it intensifies the positive impact of RT on the overall survival in cases with positive internal mammary lymph nodes. There are two types of IMRT: forward-planned IMRT (FP-IMRT) and inverse-planned IMRT (IP-IMRT). Both of them may achieve a similar plan quality to IMRT and are considered as more suitable for lymph node irradiation [69].

5.3.5. Volumetric Modulated Arc Therapy

Volumetric modulated arc therapy (VMAT) represents another modern RT technique that is optimal for left BC cases. VMAT is an IP-IMRT technique that combines the variation in gantry rotation speed, the on-treatment movement of MLC leaves, and the delivery of radiation in less time by rotating the machine around the patient. Studies have shown that VMAT is beneficial for left-sided BC patients by administering lower doses to healthy tissues, including the heart and coronary arteries, and avoiding the induced cardiac dysfunction [36]. In 2021,Zhang et al. enrolled 30 patients undergoing RT after a mastectomy [81].Compared to IMRT, VMAT treatment plans resulted in better target volume coverage and reduced heart tissue exposure to radiation.

5.3.6. Helical Tomotherapy

Another technique that belongs to the category of arc-based methods is called Tomotherapy. Tomotherapy can be further divided into axial, serial, or helical tomotherapy (HT) [82]. Studies have shown that HT reduces the MHD and the dose to LADCA by delivering RT in a continuous spiral axis [83]. However, HT is mainly recommended for patients whose treatment plan does not achieve the desirable dose limits by applying other sparing techniques to the heart tissue [84]. Indeed, in a study from Nichols GP et al., regarding 15 patients undergoing postmastectomy RT, improved OARS sparing was shown at low doses (<5Gy) with the VMAT technique compared to HT, while the latter was more effective at higher doses [37].

5.3.7. Surface-Guided Radiation Therapy

Left BC patient setup with Surface-Guided Radiation Therapy (SGRT) may improve the isocenter reproducibility in comparison to three or four tattoos [85]. The main SGRT advantage is that it utilizes thousands of points on a patient’s body and does not prolong the treatment time or clinical workflow [86]. Therefore, more accurate patient positioning and intrafractional monitoring is possible with the use of SGRT rather than lasers and the heart position deviations are smaller [85,86,87,88].

6. Conclusions

In conclusion, newer RT techniques are currently being used for preventing the development of further cardiovascular diseases in BC patients. The majority of studies have concluded that the choice of optimal treatment technique and modality depends on which of them are available in each department, as well as on individualized patient data concerning anatomy, dosimetry, and tumor characteristics. Undoubtedly, the identification of selection criteria and prognostic factors is imperative, aiming at the optimal short-term and long-term benefits for each patient.

7. Future Directions

There has clearlybeen observed an increased scientific interest in the improvement of modern available radioprotective techniques for reduced dose administration to the heart tissue and coronary vessels. However, the most effective method has yet to be determined. Despite the long latency period until the clinical interpretation of these results, a reduction in CVD morbidity and mortality is expected. Current research supports that the optimal treatment plan is based on a combination of factors, such as patient-related parameters (tumor characteristics, breast structure, a patient’s physical state, the existence of risk factors, etc.), the availability of each RT technique, and the possibility for curative-intent treatment. Consequently, several clinical questions have arisen about the use of heart-sparing techniques in everyday clinical practice. Waiting for the medical community to provide more precise answers, further well-organized studies, meta-analyses, and clinical trials have to be performed.

Author Contributions

All authors meet the criteria for authorship. There was no medical writer or editor contribution. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors have declared no conflicts of interest.

Abbreviations

Left anterior descending coronary artery: LADCA, organs at risk: OARs, Breast cancer: BC, Disability-Adjusted Life Years: DALYs, Cardiovascular disease: CVD, Three-dimensional conformal RT: 3DCRT, Mean heart dose: MHD, Left anterior descending artery: LAD, Left ventricle: LV, Radiotherapy induced cardiotoxicity: RICT, Deep-inspiration breath hold: DIBH, Intensity modulated RT: IMRT, Volumetric-modulated arc therapy: VMAT, Voluntary DIBH: vDIBH, Involuntary or moderate DIBH: iDIBH, Breath adapting radiotherapy: BART, Enhanced inspiration gating: EIG, Proton Beam Therapy: PBT, Fix forward planned IMRT: FP-IMRT, Inverse planned IMRT: IP-IMRT, Fixed proton beamlines: FBLs, Helical tomotherapy: HT, Cardiac troponin T: cTnT, Cardiac troponin I: cTnI, B-type natriuretic peptide: BNP, N-terminal pro B-type natriuretic peptide: NT-proBNP, Reactive oxygen species: ROS, Reactive nitrogen species: RNS, Caffeic acid phenethyl ester: CAPE.

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
  2. Anderson, B.; World Health Organisation. Breast Cancer. Available online: https://www.who.int/news-room/fact-sheets/detail/breast-cancer (accessed on 26 March 2021).
  3. Fahad Ullah, M. Breast Cancer: Current Perspectives on the Disease Status. In Breast Cancer Metastasis and Drug Resistance; Ahmad, A., Ed.; Advances in Experimental Medicine and Biology; Springer: Cham, Switzerland, 2019; Volume 1152. [Google Scholar] [CrossRef]
  4. Barbara, R.-C.; Piotr, R.; Kornel, B.; Elżbieta, Z.; Danuta, R.; Eduardo, N. Divergent Impact of Breast Cancer Laterality on Clinicopathological, Angiogenic, and Hemostatic Profiles: A Potential Role of Tumor Localization in Future Outcomes. J. Clin. Med. 2020, 9, 1708. [Google Scholar] [CrossRef]
  5. Mokone-Fatunla, D.H.; Koto, M.Z.; Becker, J.H.R.; Bondo, M.; Mundawarara, S. Laterality of breast cancer at Dr George Mukhari Academic Hospital. S. Afr. J. Surg. 2019, 57, 56–61. [Google Scholar] [CrossRef] [PubMed]
  6. Amer, M.H. Genetic factors and breast cancer laterality. Cancer Manag. Res. 2014, 6, 191–203. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Hennequin, C.; Barillot, I.; Azria, D.; Belkacémi, Y.; Bollet, M.; Chauvet, B.; Cowen, D.; Cutuli, B.; Fourquet, A.; Hannoun-Lévi, J.; et al. Radiothérapie du cancer du sein [Radiotherapy of breast cancer]. Cancer Radiother. 2016, 20, S139–S146. [Google Scholar] [CrossRef] [PubMed]
  8. Nitsche, M.; Pahl, R.; Huber, K.; Eilf, K.; Dunst, J. Cardiac Toxicity after Radiotherapy for Breast Cancer: Myths and Facts. Breast Care 2015, 10, 131–135. [Google Scholar] [CrossRef] [Green Version]
  9. Pfeffer, R.M. Radiotherapy for Breast Cancer: Curing the Cancer While Protecting the Heart. Isr. Med. Assoc. J. 2018, 20, 582–583. [Google Scholar]
  10. Henson, K.E.; McGale, P.; Darby, S.C.; Parkin, M.; Wang, Y.; Taylor, C.W. Cardiac mortality after radiotherapy, chemotherapy and endocrine therapy for breast cancer: Cohort study of 2 million women from 57 cancer registries in 22 countries. Int. J. Cancer 2020, 147, 1437–1449. [Google Scholar] [CrossRef] [PubMed]
  11. Rygiel, K. Cardiotoxic effects of radiotherapy and strategies to reduce them in patients with breast cancer: An overview. J. Cancer Res. Ther. 2017, 13, 186–192. [Google Scholar] [CrossRef]
  12. Lee, M.S.; Finch, W.; Mahmud, E. Cardiovascular Complications of Radiotherapy. Am. J. Cardiol. 2013, 112, 1688–1696. [Google Scholar] [CrossRef]
  13. Darby, S.C.; Ewertz, M.; McGale, P.; Bennet, A.M.; Blom-Goldman, U.; Brønnum, D.; Correa, C.; Cutter, D.; Gagliardi, G.; Gigante, B.; et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N. Engl. J. Med. 2013, 368, 987–998. [Google Scholar] [CrossRef] [Green Version]
  14. Piroth, M.D.; Baumann, R.; Budach, W.; Dunst, J.; Feyer, P.; Fietkau, R.; Haase, W.; Harms, W.; Hehr, T.; Krug, D.; et al. Heart toxicity from breast cancer radiotherapy: Current findings, assessment, and prevention. Strahlenther. und Onkol. 2018, 195, 1–12. [Google Scholar] [CrossRef] [Green Version]
  15. Abdou, Y.; Gupta, M.; Asaoka, M.; Attwood, K.; Mateusz, O.; Gandhi, S.; Takabe, K. Left sided breast cancer is associated with aggressive biology and worse outcomes than right sided breast cancer. Sci. Rep. 2022, 12, 13377. [Google Scholar] [CrossRef]
  16. Sakyanun, P.; Saksornchai, K.; Nantavithya, C.; Chakkabat, C.; Shotelersuk, K. The effect of deep inspiration breath-hold technique on left anterior descending coronary artery and heart dose in left breast irradiation. Radiat. Oncol. J. 2020, 38, 181–188. [Google Scholar] [CrossRef]
  17. Gaasch, A.; Schönecker, S.; Simonetto, C.; Eidemüller, M.; Pazos, M.; Reitz, D.; Rottler, M.; Freislederer, P.; Braun, M.; Würstlein, R.; et al. Heart sparing radiotherapy in breast cancer: The importance of baseline cardiac risks. Radiat. Oncol. 2020, 15, 117. [Google Scholar] [CrossRef] [PubMed]
  18. Łukasiewicz, S.; Czeczelewski, M.; Forma, A.; Baj, J.; Sitarz, R.; Stanisławek, A. Breast Cancer—Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies—An Updated Review. Cancers 2021, 13, 4287. [Google Scholar] [CrossRef]
  19. Budny, A.; Starosławska, E.; Budny, B.; Wójcik, R.; Hys, M.; Kozłowski, P.; Budny, W.; Brodzik, A.; Burdan, F. Epidemiologiaorazdi-agnostykarakapiersi [Epidemiology and diagnosis of breast cancer]. Pol. Merkur Lek. 2019, 46, 195–204. [Google Scholar]
  20. Kruk, J.; Aboul-Enein, H.Y. Psychological stress and the risk of breast cancer: A case–control study. Cancer Detect. Prev. 2004, 28, 399–408. [Google Scholar] [CrossRef] [PubMed]
  21. Haussmann, J.; Budach, W.; Nestle-Krämling, C.; Wollandt, S.; Tamaskovics, B.; Corradini, S.; Bölke, E.; Krug, D.; Fehm, T.; Ruckhäberle, E.; et al. Predictive Factors of Long-Term Survival after Neoadjuvant Radiotherapy and Chemotherapy in High-Risk Breast Cancer. Cancers 2022, 14, 4031. [Google Scholar] [CrossRef] [PubMed]
  22. Padegimas, A.; Clasen, S.; Ky, B. Cardioprotective strategies to prevent breast cancer therapy-induced cardiotoxicity. Trends Cardiovasc. Med. 2020, 30, 22–28. [Google Scholar] [CrossRef]
  23. Demirci, S.; Nam, J.; Hubbs, J.L.; Nguyen, T.; Marks, L.B. Radiation-Induced Cardiac Toxicity After Therapy for Breast Cancer: Interaction Between Treatment Era and Follow-Up Duration. Int. J. Radiat. Oncol. Biol. Phys. 2009, 73, 980–987. [Google Scholar] [CrossRef] [PubMed]
  24. Ferdinand, S.; Mondal, M.; Mallik, S.; Goswami, J.; Das, S.; Manir, K.S.; Sen, A.; Palit, S.; Sarkar, P.; Mondal, S.; et al. Dosimetric analysis of Deep Inspiratory Breath-hold technique (DIBH) in left-sided breast cancer radiotherapy and evaluation of pre-treatment predictors of cardiac doses for guiding patient selection for DIBH. Tech. Innov. Patient Support Radiat. Oncol. 2021, 17, 25–31. [Google Scholar] [CrossRef] [PubMed]
  25. Edvardsson, A.; Nilsson, M.P.; Amptoulach, S.; Ceberg, S. Comparison of doses and NTCP to risk organs with enhanced inspiration gating and free breathing for left-sided breast cancer radiotherapy using the AAA algorithm. Radiat. Oncol. 2015, 10, 84. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Varga, Z.; Cserháti, A.; Rárosi, F.; Boda, K.; Gulyás, G.; Együd, Z.; Kahán, Z. Individualized positioning for maximum heart protection during breast irradiation. Acta Oncol. 2014, 53, 58–64. [Google Scholar] [CrossRef] [Green Version]
  27. Tang, L.; Ishikawa, Y.; Ito, K.; Yamamoto, T.; Umezawa, R.; Jingu, K. Evaluation of DIBH and VMAT in Hypofractionated Radiotherapy for Left-Sided Breast Cancers After Breast-Conserving Surgery: A Planning Study. Technol. Cancer Res. Treat. 2021, 20, 15330338211048706. [Google Scholar] [CrossRef]
  28. Zhang, Y.; Huang, Y.; Ding, S.; Yuan, X.; Shu, Y.; Liang, J.; Mao, Q.; Jiang, C.; Li, J. A dosimetric and radiobiological evaluation of VMAT following mastectomy for patients with left-sided breast cancer. Radiat. Oncol. 2021, 16, 171. [Google Scholar] [CrossRef]
  29. Nichols, G.P.; Fontenot, J.D.; Gibbons, J.P.; Sanders, M. Evaluation of volumetric modulated Arc therapy for postmastectomy treatment. Radiat. Oncol. 2014, 9, 66. [Google Scholar] [CrossRef] [Green Version]
  30. Luo, L.; Cuaron, J.; Braunstein, L.; Gillespie, E.; Kahn, A.; McCormick, B.; Mah, D.; Chon, B.; Tsai, H.; Powell, S.; et al. Early outcomes of breast cancer patients treated with post-mastectomy uniform scanning proton therapy. Radiother. Oncol. 2019, 132, 250–256. [Google Scholar] [CrossRef]
  31. Nguyen, M.H.; Lavilla, M.; Kim, J.N.; Fang, L.C. Cardiac sparing characteristics of internal mammary chain radiotherapy using deep inspiration breath hold for left-sided breast cancer. Radiat. Oncol. 2018, 13, 103. [Google Scholar] [CrossRef]
  32. Díaz-Gavela, A.A.; Figueiras-Graillet, L.; Luis, M.; Segura, J.S.; Ciérvide, R.; Peñalver, E.d.C.; Couñago, F.; Arenas, M.; López-Fernández, T. Breast Radiotherapy-Related Cardiotoxicity. When, How, Why. Risk Prevention and Control Strategies. Cancers 2021, 13, 1712. [Google Scholar] [CrossRef]
  33. Gkantaifi, A.; Papadopoulos, C.; Spyropoulou, D.; Toumpourleka, M.; Iliadis, G.; Kardamakis, D.; Nikolaou, M.; Tsoukalas, N.; Kyrgias, G.; Tolia, M. Breast Radiotherapy and Early Adverse Cardiac Effects. The Role of Serum Biomarkers and Strain Echocardiography. Anticancer Res. 2019, 39, 1667–1673. [Google Scholar] [CrossRef] [Green Version]
  34. Sawaya, H.; Sebag, I.A.; Plana, J.C.; Januzzi, J.L.; Ky, B.; Tan, T.C.; Cohen, V.; Banchs, J.; Carver, J.R.; Wiegers, S.E.; et al. Assessment of Echocardiography and Biomarkers for the Extended Prediction of Cardiotoxicity in Patients Treated With Anthracyclines, Taxanes, and Trastuzumab. Circ. Cardiovasc. Imaging 2012, 5, 596–603. [Google Scholar] [CrossRef] [Green Version]
  35. Bottinor, W.J.; Migliore, C.K.; Lenneman, C.A.; Stoddard, M.F. Echocardiographic Assessment of Cardiotoxic Effects of Cancer Therapy. Curr. Cardiol. Rep. 2016, 18, 99. [Google Scholar] [CrossRef]
  36. Kato, T.S.; Noda, A.; Izawa, H.; Yamada, A.; Obata, K.; Nagata, K.; Iwase, M.; Murohara, T.; Yokota, M. Discrimination of Nonobstructive Hypertrophic Cardiomyopathy From Hypertensive Left Ventricular Hypertrophy on the Basis of Strain Rate Imaging by Tissue Doppler Ultrasonography. Circulation 2004, 110, 3808–3814. [Google Scholar] [CrossRef] [Green Version]
  37. Minoshima, M.; Noda, A.; Nishizawa, T.; Hara, Y.; Sugiura, M.; Iino, S.; Nagata, K.; Koike, Y.; Murohara, T. Endomyocardial Radial Strain Imaging and Left Ventricular Relaxation Abnormalities in Patients With Hypertrophic Cardiomyopathy or Hypertensive Left Ventricular Hypertrophy. Circ. J. 2009, 73, 2294–2299. [Google Scholar] [CrossRef] [Green Version]
  38. Heggemann, F.; Grotz, H.; Welzel, G.; Dösch, C.; Hansmann, J.; Kraus-Tiefenbacher, U.; Attenberger, U.; Schönberg, S.O.; Borggrefe, M.; Wenz, F.; et al. Cardiac Function After Multimodal Breast Cancer Therapy Assessed With Functional Magnetic Resonance Imaging and Echocardiography Imaging. Int. J. Radiat. Oncol. Biol. Phys. 2015, 93, 836–844. [Google Scholar] [CrossRef] [PubMed]
  39. Lo, Q.; Hee, L.; Batumalai, V.; Allman, C.; MacDonald, P.; Delaney, G.P.; Lonergan, D.; Thomas, L. Subclinical Cardiac Dysfunction Detected by Strain Imaging During Breast Irradiation With Persistent Changes 6 Weeks After Treatment. Int. J. Radiat. Oncol. Biol. Phys. 2015, 92, 268–276. [Google Scholar] [CrossRef] [PubMed]
  40. Pudil, R.; Mueller, C.; Čelutkienė, J.; Henriksen, P.A.; Lenihan, D.; Dent, S.; Barac, A.; Stanway, S.; Moslehi, J.; Suter, T.M.; et al. Role of serum biomarkers in cancer patients receiving cardiotoxic cancer therapies: A position statement from the Cardio-Oncology Study Group of the Heart Failure Association and the Cardio-Oncology Council of the European Society of Cardiology. Eur. J. Heart Fail. 2020, 22, 1966–1983. [Google Scholar] [CrossRef]
  41. Podlesnikar, T.; Berlot, B.; Dolenc, J.; Goričar, K.; Marinko, T. Radiotherapy-Induced Cardiotoxicity: The Role of Multimodality Cardiovascular Imaging. Front. Cardiovasc. Med. 2022, 9, 887705. [Google Scholar] [CrossRef]
  42. Zhang, C.; Shi, D.; Yang, P. BNP as a potential biomarker for cardiac damage of breast cancer after radiotherapy: A meta-analysis. Medicine 2019, 98, e16507. [Google Scholar] [CrossRef] [PubMed]
  43. Lyon, A.R.; López-Fernández, T.; Couch, L.S.; Asteggiano, R.; Aznar, M.C.; Bergler-Klein, J.; Boriani, G.; Cardinale, D.; Cordoba, R.; Cosyns, B.; et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur. Heart J. 2022, 43, 4229–4361. [Google Scholar] [CrossRef]
  44. Ping, Z.; Peng, Y.; Lang, H.; Xinyong, C.; Zhiyi, Z.; Xiaocheng, W.; Hong, Z.; Liang, S. Oxidative Stress in Radiation-Induced Cardiotoxicity. Oxidative Med. Cell. Longev. 2020, 2020, 3579143. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Musa, A.E.; Shabeeb, D. Radiation-Induced Heart Diseases: Protective Effects of Natural Products. Medicina 2019, 55, 126. [Google Scholar] [CrossRef] [Green Version]
  46. De, A.; Kuppusamy, G. Metformin in breast cancer: Preclinical and clinical evidence. Curr. Probl. Cancer 2020, 44, 100488. [Google Scholar] [CrossRef]
  47. Ding, Y.; Zhou, Y.; Ling, P.; Feng, X.; Luo, S.; Zheng, X.; Little, P.J.; Xu, S.; Weng, J. Metformin in cardiovascular diabetology: A focused review of its impact on endothelial function. Theranostics 2021, 11, 9376–9396. [Google Scholar] [CrossRef] [PubMed]
  48. Park, J.-W.; Park, J.-E.; Kim, S.-R.; Sim, M.-K.; Kang, C.-M.; Kim, K.S. Metformin alleviates ionizing radiation-induced senescence by restoring BARD1-mediated DNA repair in human aortic endothelial cells. Exp. Gerontol. 2022, 160, 111706. [Google Scholar] [CrossRef] [PubMed]
  49. Yu, J.-M.; Hsieh, M.-C.; Qin, L.; Zhang, J.; Wu, S.-Y. Metformin reduces radiation-induced cardiac toxicity risk in patients having breast cancer. Am. J. Cancer Res. 2019, 9, 1017–1026. [Google Scholar]
  50. Joo, J.H.; Kim, S.S.; Ahn, S.D.; Kwak, J.; Jeong, C.; Ahn, S.-H.; Son, B.-H.; Lee, J.W. Cardiac dose reduction during tangential breast irradiation using deep inspiration breath hold: A dose comparison study based on deformable image registration. Radiat. Oncol. 2015, 10, 264. [Google Scholar] [CrossRef] [Green Version]
  51. Saini, A.S.; Hwang, C.S.; Biagioli, M.C.; Das, I.J. Evaluation of sparing organs at risk (OARs) in left-breast irradiation in the supine and prone positions and with deep inspiration breath-hold. J. Appl. Clin. Med. Phys. 2018, 19, 195–204. [Google Scholar] [CrossRef]
  52. Koutroumpakis, E.; Palaskas, N.L.; Lin, S.H.; Abe, J.-I.; Liao, Z.; Banchs, J.; Deswal, A.; Yusuf, S.W. Modern Radiotherapy and Risk of Cardiotoxicity. Chemotherapy 2020, 65, 65–76. [Google Scholar] [CrossRef]
  53. Schönecker, S.; Walter, F.; Freislederer, P.; Marisch, C.; Scheithauer, H.; Harbeck, N.; Corradini, S.; Belka, C. Treatment planning and evaluation of gated radiotherapy in left-sided breast cancer patients using the CatalystTM/SentinelTM system for deep inspiration breath-hold (DIBH). Radiat. Oncol. 2016, 11, 143. [Google Scholar] [CrossRef] [Green Version]
  54. Bergom, C.; Currey, A.; Desai, N.; Tai, A.; Strauss, J. Deep Inspiration Breath Hold: Techniques and Advantages for Cardiac Sparing During Breast Cancer Irradiation. Front. Oncol. 2018, 8, 87. [Google Scholar] [CrossRef] [Green Version]
  55. Berg, M.; Lorenzen, E.L.; Jensen, I.; Thomsen, M.S.; Lutz, C.M.; Refsgaard, L.; Nissen, H.D.; Offersen, B.V. The potential benefits from respiratory gating for breast cancer patients regarding target coverage and dose to organs at risk when applying strict dose limits to the heart: Results from the DBCG HYPO trial. Acta Oncol. 2018, 57, 113–119. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Trivedi, S.J.; Tang, S.; Byth, K.; Stefani, L.; Lo, Q.; Otton, J.; Jameson, M.; Tran, D.; Batumalai, V.; Holloway, L.; et al. Segmental Cardiac Radiation Dose Determines Magnitude of Regional Cardiac Dysfunction. J. Am. Heart Assoc. 2021, 10, e019476. [Google Scholar] [CrossRef]
  57. Walker, V.; Lairez, O.; Fondard, O.; Jimenez, G.; Camilleri, J.; Panh, L.; Broggio, D.; Bernier, M.-O.; Laurier, D.; Ferrières, J.; et al. Myocardial deformation after radiotherapy: A layer-specific and territorial longitudinal strain analysis in a cohort of left-sided breast cancer patients (BACCARAT study). Radiat. Oncol. 2020, 15, 201. [Google Scholar] [CrossRef] [PubMed]
  58. Wang, X.; Fargier-Bochaton, O.; Dipasquale, G.; Laouiti, M.; Kountouri, M.; Gorobets, O.; Nguyen, N.P.; Miralbell, R.; Vinh-Hung, V. Is prone free breathing better than supine deep inspiration breath-hold for left whole-breast radiotherapy? A dosimetric analysis. Strahlenther. Onkol. 2021, 197, 317–331. [Google Scholar] [CrossRef] [PubMed]
  59. Bergom, C.; Bradley, J.A.; Ng, A.K.; Samson, P.; Robinson, C.; Lopez-Mattei, J.; Mitchell, J.D. Past, Present, and Future of Radiation-Induced Cardiotoxicity: Refinements in Targeting, Surveillance, and Risk Stratification. JACC CardioOncology 2021, 3, 343–359. [Google Scholar] [CrossRef] [PubMed]
  60. Skyttä, T.; Tuohinen, S.; Boman, E.; Virtanen, V.; Raatikainen, P.; Kellokumpu-Lehtinen, P.-L. Troponin T-release associates with cardiac radiation doses during adjuvant left-sided breast cancer radiotherapy. Radiat. Oncol. 2015, 10, 141. [Google Scholar] [CrossRef] [Green Version]
  61. Gkantaifi, A.; Papadopoulos, C.; Spyropoulou, D.; Toumpourleka, M.; Iliadis, G.; Tsoukalas, N.; Kyrgias, G.; Tolia, M. Evaluation of the Irradiated Volume of the Heart and Cardiac Substructures After Left Breast Radiotherapy. Anticancer Res. 2020, 40, 3003–3009. [Google Scholar] [CrossRef]
  62. Falco, M.; Masojć, B.; Macała, A.; Łukowiak, M.; Woźniak, P.; Malicki, J. Deep inspiration breath hold reduces the mean heart dose in left breast cancer radiotherapy. Radiol. Oncol. 2021, 55, 212–220. [Google Scholar] [CrossRef]
  63. Lai, J.M.; Zhong, F.M.; Deng, J.M.; Hu, S.B.; Shen, R.B.; Luo, H.; Luo, Y.B. Prone position versus supine position in postoperative radiotherapy for breast cancer. Medicine 2021, 100, e26000. [Google Scholar] [CrossRef]
  64. Kirby, A.M.; Evans, P.; Donovan, E.; Convery, H.M.; Haviland, J.; Yarnold, J.R. Prone versus supine positioning for whole and partial-breast radiotherapy: A comparison of non-target tissue dosimetry. Radiother. Oncol. 2010, 96, 178–184. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Varga, Z.; Hideghéty, K.; Mező, T.; Nikolényi, A.; Thurzó, L.; Kahán, Z. Individual Positioning: A Comparative Study of Adjuvant Breast Radiotherapy in the Prone Versus Supine Position. Int. J. Radiat. Oncol. Biol. Phys. 2009, 75, 94–100. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Griem, K.L.; Fetherston, P.; Kuznetsova, M.; Foster, G.S.; Shott, S.; Chu, J. Three-dimensional photon dosimetry: A comparison of treatment of the intact breast in the supine and prone position. Int. J. Radiat. Oncol. Biol. Phys. 2003, 57, 891–899. [Google Scholar] [CrossRef] [PubMed]
  67. Chung, Y.; Yu, J.I.; Park, W.; Choi, D.H. Korean First Prospective Phase II Study, Feasibility of Prone Position in Postoperative Whole Breast Radiotherapy: A Dosimetric Comparison. Cancer Res. Treat. 2019, 51, 1370–1379. [Google Scholar] [CrossRef] [Green Version]
  68. Kahán, Z.; Rárosi, F.; Gaál, S.; Cserháti, A.; Boda, K.; Darázs, B.; Kószó, R.; Lakosi, F.; Gulybán, Á.; Coucke, P.A.; et al. A simple clinical method for predicting the benefit of prone vs. supine positioning in reducing heart exposure during left breast radiotherapy. Radiother. Oncol. 2018, 126, 487–492. [Google Scholar] [CrossRef]
  69. Stowe, H.B.; Andruska, N.D.; Reynoso, F.; Thomas, M.; Bergom, C. Heart Sparing Radiotherapy Techniques in Breast Cancer: A Focus on Deep Inspiration Breath Hold. Breast Cancer Targets Ther. 2022, 14, 175–186. [Google Scholar] [CrossRef] [PubMed]
  70. Lu, Y.; Yang, D.; Zhang, X.; Teng, Y.; Yuan, W.; Zhang, Y.; He, R.; Tang, F.; Pang, J.; Han, B.; et al. Comparison of Deep Inspiration Breath Hold Versus Free Breathing in Radiotherapy for Left Sided Breast Cancer. Front. Oncol. 2022, 12, 845037. [Google Scholar] [CrossRef]
  71. Desai, N.; Currey, A.; Kelly, T.; Bergom, C. Nationwide Trends in Heart-Sparing Techniques Utilized in Radiation Therapy for Breast Cancer. Adv. Radiat. Oncol. 2019, 4, 246–252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Ferini, G.; Molino, L.; Tripoli, A.; Valenti, V.; Illari, S.I.; Marchese, V.A.; Cravagno, I.R.; Borzi, G.R. Anatomical Predictors of Dosimetric Advantages for Deep-inspiration-breath-hold 3D-conformal Radiotherapy Among Women With Left Breast Cancer. Anticancer Res. 2021, 41, 1529–1538. [Google Scholar] [CrossRef]
  73. Taylor, C.; Correa, C.; Duane, F.K.; Aznar, M.C.; Anderson, S.J.; Bergh, J.; Dodwell, D.; Ewertz, M.; Gray, R.; Jagsi, R.; et al. Estimating the Risks of Breast Cancer Radiotherapy: Evidence From Modern Radiation Doses to the Lungs and Heart and From Previous Randomized Trials. J. Clin. Oncol. 2017, 35, 1641–1649. [Google Scholar] [CrossRef]
  74. Ferini, G.; Valenti, V.; Viola, A.; Umana, G.E.; Martorana, E. A Critical Overview of Predictors of Heart Sparing by Deep-Inspiration-Breath-Hold Irradiation in Left-Sided Breast Cancer Patients. Cancers 2022, 14, 3477. [Google Scholar] [CrossRef]
  75. Ferini, G.; Molino, L. Hypothesis of a decision-making algorithm for adjuvant radiotherapy in left-sided breast cancer patients. Tech. Innov. Patient Support Radiat. Oncol. 2021, 20, 64–65. [Google Scholar] [CrossRef]
  76. Marc, L.; Fabiano, S.; Wahl, N.; Linsenmeier, C.; Lomax, A.J.; Unkelbach, J. Combined proton–photon treatment for breast cancer. Phys. Med. Biol. 2021, 66, 235002. [Google Scholar] [CrossRef] [PubMed]
  77. Hug, E.B. Proton Therapy for Primary Breast Cancer. Breast Care 2018, 13, 168–172. [Google Scholar] [CrossRef]
  78. Musielak, M.; Suchorska, W.M.; Fundowicz, M.; Milecki, P.; Malicki, J. Future Perspectives of Proton Therapy in Minimizing the Toxicity of Breast Cancer Radiotherapy. J. Pers. Med. 2021, 11, 410. [Google Scholar] [CrossRef]
  79. Adeneye, S.; Akpochafor, M.; Adegboyega, B.; Alabi, A.; Adedewe, N.; Joseph, A.; Fatiregun, O.; Omojola, A.; Adebayo, A.; Oluwadara, E. Evaluation of Three-Dimensional Conformal Radiotherapy and Intensity Modulated Radiotherapy Techniques for Left Breast Post-Mastectomy Patients: Our Experience in Nigerian Sovereign Investment Authority-Lagos University Teaching Hospital Cancer Center, South-West Nigeria. Eur. J. Breast Health 2021, 17, 247–252. [Google Scholar] [CrossRef] [PubMed]
  80. Shanei, A.; Amouheidari, A.; Abedi, I.; Kazemzadeh, A.; Jaafari, A. Radiobiological comparison of 3D conformal and intensity modulated radiation therapy in the treatment of left-sided breast cancer. Int. J. Radiat. Res. 2020, 18, 315–322. [Google Scholar]
  81. Figlia, V.; Simonetto, C.; Eidemüller, M.; Naccarato, S.; Sicignano, G.; De Simone, A.; Ruggieri, R.; Mazzola, R.; Matuschek, C.; Bölke, E.; et al. Mammary Chain Irradiation in Left-Sided Breast Cancer: Can We Reduce the Risk of Secondary Cancer and Ischaemic Heart Disease with Modern Intensity-Modulated Radiotherapy Techniques? Breast Care 2021, 16, 358–367. [Google Scholar] [CrossRef]
  82. Teoh, M.; Clark, C.H.; Wood, K.; Whitaker, S.; Nisbet, A. Volumetric modulated arc therapy: A review of current literature and clinical use in practice. Br. J. Radiol. 2011, 84, 967–996. [Google Scholar] [CrossRef] [PubMed]
  83. Yeh, H.-P.; Huang, Y.-C.; Wang, L.-Y.; Shueng, P.-W.; Tien, H.-J.; Chang, C.-H.; Chou, S.-F.; Hsieh, C.-H. Helical tomotherapy with a complete-directional-complete block technique effectively reduces cardiac and lung dose for left-sided breast cancer. Br. J. Radiol. 2020, 93, 20190792. [Google Scholar] [CrossRef] [PubMed]
  84. Mathieu, D.; Bedwani, S.; Mascolo-Fortin, J.; Côté, N.; Bernard, A.-A.; Roberge, D.; Yassa, M.; Bahig, H.; Vu, T. Cardiac Sparing with Personalized Treatment Planning for Early-stage Left Breast Cancer. Cureus 2020, 12, e7247. [Google Scholar] [CrossRef] [Green Version]
  85. Laaksomaa, M.; Ahlroth, J.; Pynnönen, K.; Murtola, A.; Rossi, M.E. AlignRT®, Catalyst™ and RPM™ in locoregional radiotherapy of breast cancer with DIBH. Is IGRT still needed? Rep. Pr. Oncol. Radiother. 2022, 27, 797–808. [Google Scholar] [CrossRef]
  86. Kost, S.; Guo, B.; Xia, P.; Shah, C. Assessment of Setup Accuracy Using Anatomical Landmarks for Breast and Chest Wall Irradiation With Surface Guided Radiation Therapy. Pr. Radiat. Oncol. 2019, 9, 239–247. [Google Scholar] [CrossRef] [PubMed]
  87. Svestad, J.G.; Heydari, M.; Mikalsen, S.G.; Flote, V.G.; Nordby, F.; Hellebust, T.P. Surface-guided positioning eliminates the need for skin markers in radiotherapy of right sided breast cancer: A single center randomized crossover trial. Radiother. Oncol. 2022, 177, 46–52. [Google Scholar] [CrossRef] [PubMed]
  88. Lu, W.; Li, G.; Hong, L.; Yorke, E.; Tang, X.; Mechalakos, J.G.; Zhang, P.; Cerviño, L.I.; Powell, S.; Berry, S.L. Reproducibility of chestwall and heart position using surface-guided versus RPM-guided DIBH radiotherapy for left breast cancer. J. Appl. Clin. Med. Phys. 2023, 24, e13755. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Dosimetry of the dose distribution for breast cancer radiotherapy techniques, considering the parameters of the mean dose and maximum dose regarding the heart and LADCA.
Table 1. Dosimetry of the dose distribution for breast cancer radiotherapy techniques, considering the parameters of the mean dose and maximum dose regarding the heart and LADCA.
First AuthorNumber of Treated PatientsTargetDelivery TechniqueDmean/heart (Gy)Dmax/heart
(Gy)		Dmean/LADCA
(Gy)		Dmax/LADCA
(Gy)		pvalue
Ferdinand S et al. [24]31
(Comparison of both techniques in the same patients, before treatment)		Breast or CW in left-sided BC patients after BCS and in those with high RFs after MRMFB/DIBH439.412.631.939.15%reduction in mean heart dose in DIBH compared to FB(2.4 Gy vs. 4.01Gy)
p < 0.001
2.431.58.725.819% reduction in maximum LAD dose and a 9.9% reduction in ipsilateral lung mean dose p = 0.036
Edvardsson A et al. [25]32
(Comparison of both techniques in the same patients, before treatment)		16 patients: tangential breast irradiation to the WB after lumpectomy,
9 patients: locoregional RT after lumpectomy,
7 patients: locoregional RT after mastectomy		FB/EIG3.1-25.4-Median V25Gy for heart, LAD decreased for EIG (2.2 to 0.2% and 40.2 to 0.1%, respectively) (p < 0.001)
1.5-8.0-MedianV25heart and LAD decreased for EIG (3.3 to 0.2% and 51.4 to 5.1%, respectively(p < 0.001)
Varga Z et al. [26]83
(Comparison of both positions in the same patients, before treatment)		3D-Conformal RT in left-sided BC patients.Prone/SupineProne 2.18 ± 0.15
/Supine 2.89 ± 0.19		-Prone 11.06 ± 0.79/
Supine 13.7 ± 0.79
-Mean Heart Dose:
Prone 2.18 ± 0.15
Supine
2.89 ± 0.19
<0.001
LAD Mean dose:
11.06 ± 0.79/
Supine 13.7 ± 0.79
p value = 0.014
Tang L et al. [27]11Left-sided BC patients after BCSDIBH-3DCRT/FB-3DCRT0.88/1.5213.80/29.332.21/3.045.94/12.29DIBH-3DCRT, dose reductions in all evaluation parameters of the heart and LADCA compared with those in the FB (p < 0.05).
All patients were compared in FB and DIBH positions and in
3DCRT and VMAT techniques		Whole Breast
DB-VMAT0.475.321.433.76DIBH–VMAT dose reductions in heart and LADCA compared to 3DCRT plans (p < 0.05).
Zhang Y et al. [28]30
(Both IMRT and VMAT plans were created for each patient)		CW and IMN in left-sided BC patients after radical mastectomyIMRT/
VMAT		12.6 ± 0.7/11.5 ± 0.7---≤0.002
Nichols GP [29]15
(Both HT and VMAT plans were created for each patient)		CW and RLN after mastectomy and previously treated with HT (7 patients: bilateral CW and 8 patients: left CW)HT/VMAT14.4 ± 0.6/12.9 ± 0.5--42.2 ± 1.6/38.3 ± 1.3<0.05
Luo L. et al. [30]36
All patients received proton therapy		Postmastectomy WB in left-sided BC3DCPT
FB/DIBH		0.84 Gy (RBE) (range 0–3.2 Gy)3.2 Gy (RBE)---
Nguyen MH et al. [31]49
(All patients were compared with both FB and DIBH treatment plans)		Left-sided BC patients after mastectomy or BCS
49 of whom received RNI		FB/DIBHIMN treated6.73---DIBH reduced the average mean heart dose from 6.73 Gy to 2.79 Gy in the IMN treated group and from 4.77 Gy to 1.55 Gy in the IMN untreated group compared to FB technique
(both p  <  0.001).
IMN untreated4.77---
IMN treated2.79---
IMN untreated1.55---
Sakyanun P et al. [16]25
(All plans were created with FB and DIBH techniques and four radiation treatment plans)		WB, WB, and IMN in left-sided BC patients after BCSFB/
DIBH		IMN treated10.24-31.98-<0.0001
IMN untreated5.38-19.84-<0.0001
IMN treated6.43-23.88-<0.0001
IMN untreated2.95-11.48-<0.0001
Abbreviations:CW, chest wall; BC, breast cancer; RFs, risk factors; BCS, breast conservation surgery; MRM, modified radical mastectomy; FB, free breathing; DIBH, deep-inspiration breath hold; EIG, enhanced inspiration gating; WB, whole breast; RT, radiotherapy; 3DCRT, three-dimensional conformal radiotherapy; DB, deep breathing; VMAT, volumetric modulated arc therapy; IMN, internal mammary nodes; IMRT, intensity modulated RT; RLN, regional lymph nodes; HT, helical tomotherapy; 3DCPT, three-dimensional conformal proton therapy; RNI, regional node irradiation; and LADCA: left anterior descending coronary artery. Dmean/heart (whole heart mean dose in Gy), Dmax/heart (whole heart max dose in Gy), Dmean/LADCA (left anterior descending coronary arterymean dose in Gy), and Dmax/LAD dose(left anterior descending coronary arterymax dose in Gy).
Table
Table 2. Dosimetry of the dose distribution for breast cancer radiotherapy techniques, considering the parameters of V5 (%), V10 (%), V20 (%), V25 (%), and V40 (%) regarding the heart, and V20 (%) and V25 (%) regarding the LADCA.
Table 2. Dosimetry of the dose distribution for breast cancer radiotherapy techniques, considering the parameters of V5 (%), V10 (%), V20 (%), V25 (%), and V40 (%) regarding the heart, and V20 (%) and V25 (%) regarding the LADCA.
First AuthorDelivery TechniqueHeart V5 (%)Heart V10 (%)Heart V20 (%)Heart V25 (%)Heart V40 (%)LAD V20
(%)		LAD V25 (%)
Ferdinand S et al. [24]FB14.28.9-----
DIBH7.63.4-----
pvalue0.000.00-----
Edvardsson A et al. [25]FB---3.3--51.4
EIG---0.2--5.1
pvalue---<0.001--<0.001
Varga Z et al. [26]Prone---2.01-21.91-
Supine---3.54-29.26-
pvalue---0.010-<0.001-
Tang L et al. [27]FB-3DCRT2.68------
DB-3DCRT0.23------
DB-VMAT0.04------
pvalue<0.01------
Zhang Y et al. [28]IMRT/VMAT27.9/20.912.2/9.17.4/4.6-2.0/0.7--
pvalue<0.001<0.001<0.001-<0.001--
Luo L et al. [30]3DCPT4.3-0.5----
Nguyen MH et al. [31]FBIMN treated34.519.98.96.4---
IMN untreated19.411.66.35.0---
DIBHIMN treated12.74.11.00.4---
IMN untreated2.80.80.20.1---
pvalue <0.001<0.001<0.001<0.001---
Sakyanun P et al. [16]FBIMN treated---16.96-13.96-
IMN untreated---8.20-6.22-
DIBHIMN treated---10.37-7.50-
IMN untreated---3.48-2.48-
pvalue ---<0.0001-<0.0001-
Abbreviations: V5 (%), the percentage volume of organ receiving 5 Gy; V10 (%), the percentage volume of organ receiving 10 Gy; V20 (%), the percentage volume of organ receiving 20 Gy; V25 (%), the percentage volume of organ receiving 25 Gy; V40 (%), the percentage volume of organ receiving 40 Gy.
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Nikovia, V.; Chinis, E.; Gkantaifi, A.; Marketou, M.; Mazonakis, M.; Charalampakis, N.; Mavroudis, D.; Orfanidou, K.V.; Varveris, A.; Antoniadis, C.; et al. Current Cardioprotective Strategies for the Prevention of Radiation-Induced Cardiotoxicity in Left-Sided Breast Cancer Patients. J. Pers. Med. 2023, 13, 1038. https://doi.org/10.3390/jpm13071038

AMA Style

Nikovia V, Chinis E, Gkantaifi A, Marketou M, Mazonakis M, Charalampakis N, Mavroudis D, Orfanidou KV, Varveris A, Antoniadis C, et al. Current Cardioprotective Strategies for the Prevention of Radiation-Induced Cardiotoxicity in Left-Sided Breast Cancer Patients. Journal of Personalized Medicine. 2023; 13(7):1038. https://doi.org/10.3390/jpm13071038

Chicago/Turabian Style

Nikovia, Vasiliki, Evangelos Chinis, Areti Gkantaifi, Maria Marketou, Michalis Mazonakis, Nikolaos Charalampakis, Dimitrios Mavroudis, Kornilia Vasiliki Orfanidou, Antonios Varveris, Chrysostomos Antoniadis, and et al. 2023. "Current Cardioprotective Strategies for the Prevention of Radiation-Induced Cardiotoxicity in Left-Sided Breast Cancer Patients" Journal of Personalized Medicine 13, no. 7: 1038. https://doi.org/10.3390/jpm13071038

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