Breast Radiotherapy-Related Cardiotoxicity. When, How, Why. Risk Prevention and Control Strategies
Abstract
:Simple Summary
Abstract
1. Introduction and Background
1.1. Physiopathologic Aspects
1.2. Clinical Evidence
2. Baseline Risk Evaluation
3. Specific Risk of Cardiotoxicity in Breast Cancer Patients Receiving RT
3.1. Valvular Heart Disease
3.2. Coronary Artery Disease
3.3. Pericardiac Disease
3.4. Conduction Disorders
3.5. Myocardial Injury
3.6. Implantable Cardiac Stimulator Device Dysfunction
4. Toxicity Enhancement by Systemic Treatments
5. Risk Reduction Strategies
5.1. Control of Cardiotoxicity Factors Associated with Radiotherapy Treatment
5.1.1. Maneuvers to Separate the Heart from the Chest Wall
5.1.2. Conformal Radiation Therapy Techniques
5.1.3. Reduction in Irradiated Volumes. Accelerated Partial Breast Irradiation. Intraoperative Radiotherapy
5.2. Impact of Hypofractionated and Ultrahypofractionated Schemes on Cardiotoxicity by Radiotherapy
- n = number of fractions,
- D = total dose in Gy,
- d = dose per fraction in Gy,
- α/β = dose at which the linear and quadratic components responsible for cell death are equal. This indicates the intrinsic radiosensitivity of the tissue.
6. Potential Tools for Early Diagnosis, Monitoring, and Control of Post Breast Irradiation Heart Disease
7. Cardiac Rehabilitation in Patients after Radiotherapy
8. Future Directions
9. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Study | Type of Study | Decade of RT/ RT Modality/ Dosimetry (RT Planning Data) | N. of Patients | Issue Evaluated | Effect |
---|---|---|---|---|---|
McGale 2011 [17] | Prospective. Population-based study | 1976–2006 Various Estimated planning data | 72,134 (34,825 received RT) | Incidence of heart disease: RT vs. no RT Left vs. right RT | IR: 1.08 for left vs. right RT For acute myocardial infarction, the increase in the IR, left vs. right, was greatest at 15+ ys after RT; for angina, it was greatest at 0–4 ys; and for pericarditis and valvular heart disease, it was greatest at 5–9 ys. Significantly higher IR of CV disease if RT was before 1990 |
Darby 2013 [20] | Retrospective. Population-based case-control study | 1958–2006 Not reported Estimated planning data | 963 (cases) vs. 1208 (controls) | MCE | Per 1 Gy of MHD: Increase of RR for MCE: 7.4%/16.3% Higher risk in the left breast and patients with CVRF |
Sardar 2016 [25] | Metanalysis | ?–2015 Various Not collected | 289,109 | CV mortality after left vs. right-breast RT | RR of CV mortality: 1.12 for left versus right RT RR of CV mortality: 1.23 after 15 years of follow-up Higher RR if treatment before 1982 (RR 1.38) |
van den Bogaard 2017 [21] | Cohort. Single institution | 2005–2008 3D-RT Individual planning data | 910 | Cumulative incidence of ACEs within 9 years of follow-up. | Per 1Gy of MHD: 16.5% increase for ACEs LV-V5: 29.3% vs. 16.9%: ACE vs. no event Developed an RS for predicting ACE, including age, CVRF, and LV-V5 |
Taylor 2017 [24] | Metanalysis | 1972–1989 2D-RT Depends on the study | 40,781 | CV mortality Effect of smoking habit | RR cardiac mortality: 1.3 RT vs. no RT ↑ 4% mortality RR for each Gy of MHD Higher risk in smokers |
Cheng 2017 [22] | Metanalysis | 1980–2015 Various Not collected | 1,191,371 | CV disease CV mortality | RR CV mortality: 1.22 left vs. right RT RR CV mortality: 1.38 RT versus no RT IHD: RR 1.29 left versus right RT |
Henson 2020 [23] | Registry-based Cohort | 1987–2002 Various Not collected | 1,018,505 | Cardiac mortality | The RT- RR for cardiac mortality was greater at younger ages, lasted over 25 years, and was greater in women when ChT was also given |
Wennstig 2020 [26] | Retrospective. Population-based case-control | 1992 to 2012 3D-RT Not collected | 361,008 (60,217 with BC + 300,791 without BC) Received RT: 37427 | Risk of IHD | ↑ risk left vs. right RT (HR 1.18; HRs increased with more extensive lymph node involvement and with the addition of systemic therapy) The cumulative IHD incidence started from the first years after RT and was sustained with longer follow-up |
Louise Holm Milo 2021 [28] | Retrospective Population-based cohort | 1999–2007: Non-CT-based 2008–2016: CT-based RT | 29662 (22056 received RT) | Risk of MCE in left vs. right-sided BC patients treated during a non-CT vs. a CT-based period. | Non-CT period-> 15-year risk-difference left vs. right: p = 0.06. CT-based-> 10-year risk-difference left vs. right: p= 0.56 |
Risk Factors for Radiation-Induced Cardiovascular Complications |
---|
Lifestyle risk factors |
Current smoker |
Sedentary habit |
Obesity (BMI > 30) |
Demographic and CV risk factors |
Age ≥65 years |
Hypertension |
Diabetes mellitus ✦ |
Hyperlipidaemia Ø |
Previous cardiovascular disease |
Heart failure or cardiomyopathy |
Coronary artery disease |
Cardiac implantable electronic devices |
Previous cardiotoxic cancer treatment |
Prior anthracycline exposure (>250 mg/m2) |
Prior thoracic radiotherapy |
Cardiovascular Risk Factor | Treatment Goals | |
---|---|---|
Blood Pressure | <130/80 mmHg | |
LDL Cholesterol | Very high risk or SCORE * ≥10% | <55 mg/dl |
High risk (SCORE * ≥ 5 y < 10%) | <70 mg/dl | |
Moderate risk (SCORE * ≥ 1 y < 5%) | <100 mg/dl | |
Low risk (SCORE * < 1%) | <116 mg/dl | |
Diabetes Mellitus | HbA1c < 7% | |
Smoking | No | |
Alcohol intake | <20 g/day in men and 10 g/day in women | |
Exercise | Moderate physical activity at least 30 min/5 days a week | |
Diet | Healthy diet | |
BMI | 20–25 kg/m2 |
Cancer Treatment | Drug | VE | Myo-Is | Arryth | PDis | Myo | C-Myo | Mechanism | C-RF | ||
---|---|---|---|---|---|---|---|---|---|---|---|
Anthracycline | Doxorubicin, Epirubicin, | Yes | Yes | Yes | Oxidative stress Alteration of DNA topoisomerase | Cumulative dose → dependent π | Dose(mg/m2) | % | |||
150 | 0.2 | ||||||||||
300 | 1.7 | ||||||||||
400 | 4.7 | ||||||||||
500 | 15.7 | ||||||||||
700 | 48 | ||||||||||
Pre-existing heart disease High blood pressure Concomitant or sequential RT Age | |||||||||||
Anti-HER-2 | Trastuzumab Pertuzumab, T-DM1 | Yes | Disruption of the signal between the HER2 receptor and the neuregulin ligand. | 27% of cardiac disfunction using Anti-HER2 + anthracyclines + cyclophosphamide concomitantly | |||||||
Alkilant agents | Cyclophosphamide | Yes | Yes | Yes | Yes | Yes | DNA alkylation. | Dose-dependant (>140 mg/kg) Advanced age Bolus administration Previous RT Concomitant ChT | |||
Fluoropirimidins (antimetabolites) | Capecitabine 5-FU | Yes | Yes | Yes | Binds irreversibly to the enzyme thymidylate synthase → inhibits cell division. Endothelial injury and thrombosis Increased oxygen consumption, oxidative stress, and vasospasm favored by the release of histamine | Continuous infusion Role of deficiency in DPD? | |||||
Taxanes | Docetaxel Paclitaxel | Yes | Yes | By acting on microtubules decrease the concentration of calcium in cardiomyocytes, reducing the time from maximum contraction to relaxation | Use of AC concomitantly | ||||||
Endocrine agents | Tamoxifen | Higher thrombotic risk compared with AI | Block estrogen receptors in breast tissue | Baseline cardiovascular risk factors | |||||||
AI | Slight but higher risk of acute myocardial infarction and heart failure compared with tamoxifen. Alterations in the lipid profile | Block the enzyme aromatase | |||||||||
VEGF inhibitors | Bevacizumab | Yes | Yes | Yes | Bevacizumab binds to VEGF, inhibiting its ability to bind to and activate VEGF receptors → inhibition of angiogenesis | High-dose bevacizumab |
α/β | Variations | 50 Gy (2 Gy/Fraction) | 40.5 Gy (2.7 Gy/Fraction) | 26 Gy (5.2 Gy/Fraction) |
---|---|---|---|---|
3 Gy | EQD2 | 50 Gy | 46.2 Gy | 42.6 Gy |
BED | 83.3 Gy | 77 Gy | 71.1 Gy | |
2 Gy | EQD2 | 50 Gy | 47.6 Gy | 46.8 Gy |
BED | 100 Gy | 95.2 Gy | 93.6 Gy | |
1.5 Gy | EQD2 | 50 Gy | 48.6 Gy | 49.8 Gy |
BED | 116.7 Gy | 113.4 Gy | 116.1 Gy |
Study/ Estimated Completion Date | Official Title | Type of Study | N. of Patients | Insight | Primary Outcome Measures | Secondary Outcome Measures |
---|---|---|---|---|---|---|
NCT03211442 Nov 2022 | Implications of MEDIcal Low Dose RADiation Exposure - BReast Cancer Acute Coronary Events (MEDIRAD-BRACE): A Retrospective Cohort Study | Retrospective Cohort Study | 7000 | Externally validate multivariable NTCP models to assess the risk of ACE based on cardiac dose metrics in the first 10 ys after RT | ACE 10 ys after RT | Other cardiac complications RT-induced late non-cardiac toxicity |
NCT02541435 Dec 2036 | Acute and Long-term Cardiovascular Toxicity After Modern Radiotherapy for Breast Cancer —a Prospective Longitudinal Study | Observational. Cohort. Prospective | 1600 | Two cohorts of BC patients will be followed for the development of CVD for 15 ys | Incidence of CVD compared with corresponding estimates from the female general population 8 and 15 ys after RT | |
NCT03748030 Dec 2021 | Assessing Acute Cardiac Inflammation After Left-Sided Breast Cancer Radiotherapy With Hybrid PET/MRI | Observational. Cohort. Prospective | 15 | Identify the presence of acute low-dose RT-CVD in left-sided BC patients using hybrid PET/MRI |
| |
NCT02156648 Jul 2020 | A Feasibility Study for Women Receiving Adjuvant or Neo-adjuvant Anthracycline Chemotherapy With or Without Radiation for HER2-neu Positive Invasive Ductal Carcinoma | Interventional (Clinical Trial). Single Group Assignment | 20 | To assess the feasibility of collecting plasma samples for SBio and to identify if there is an association between the SBio, echocardiography, and cardiac PET results in irradiated patients | Recruitment rates | Cardiotoxicity. To measure SBio, MP, RT-CVD, and PSLS |
NCT04044872 Dec 2023 | Single Institution Feasibility Study to Detect Radiation-Induced Cardiotoxicity in Receiving Thoracic Radiation Patients Using Hyperpolarized Carbon 13-Based Magnetic Resonance Spectroscopic Imaging | Interventional (Clinical Trial). Single Group Assignment | 10 | The goal of this study is to detect early changes in the mitochondrial metabolism in situ as a marker for subclinical RT-CVD | To determine if RT-CVD can be measured by an increase in [1–13 C]lactate/[13 C]bicarbonate ratio and a decrease in [5–13 C]glutamate formation | Determination of the prognostic value of decreased MMPF in predicting clinically significant RT-CVD |
NCT03301389 Jan 2025 | Cardiac Magnetic Resonance for Early Detection of Chemotherapy or Radiation Therapy Induced Cardiotoxicity in Breast Cancer (CareBest) | Observational. Cohort. Prospective | 2000 | Aimed to achieve early detection of CT or RT-CVD using T1 mapping MRI. To determine a prognostic imaging factor for treatment cardiotoxicity | Decrease in left ventricular ejection fraction(LVEF) 1 and 2 ys after RT | Major adverse cardiac events (MACE) 1 and 2 ys after RT |
NCT04361240 Aug 2023 | Cardiotoxicity in Breast Cancer Patients Treated with Proton or Photon Radiotherapy: A RadComp Ancillary Cohort Study | Observational. Cohort. Prospective | 155 | The investigators will collect SBio and echocardiograms prior to, during, and for up to 1 year following radiation for a subset of patients enrolled in RadComp study (NCT02603341) | LVEF RV-FAC Circulating NTproBNP Circulating PIGF Circulating GDF-15 | Changes in:
|
NCT01758445 Jan 2030 | Phase II Study of Postoperative, Cardiac-Sparing Proton Radiotherapy for Patients With Stage II/III, Loco-Regional, Non-Metastatic Breast Cancer Requiring Whole Breast or Chest Wall Irradiation With Lymph Node Irradiation | Interventional (Clinical Trial). Single Group Assignment | 220 | The study goal is to demonstrate a “meaningful benefit” of proton therapy for women with loco-regionally advanced BC | 5-y determination of the rates of acute and late RT toxicities | To determine dose distribution of proton therapy to coronary arteries and heart. Determine the incidence of ACE, cardiac morbidity, and mortality |
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Díaz-Gavela, A.A.; Figueiras-Graillet, L.; Luis, Á.M.; Salas Segura, J.; Ciérvide, R.; del Cerro Peñalver, E.; Couñago, F.; Arenas, M.; López-Fernández, T. Breast Radiotherapy-Related Cardiotoxicity. When, How, Why. Risk Prevention and Control Strategies. Cancers 2021, 13, 1712. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071712
Díaz-Gavela AA, Figueiras-Graillet L, Luis ÁM, Salas Segura J, Ciérvide R, del Cerro Peñalver E, Couñago F, Arenas M, López-Fernández T. Breast Radiotherapy-Related Cardiotoxicity. When, How, Why. Risk Prevention and Control Strategies. Cancers. 2021; 13(7):1712. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071712
Chicago/Turabian StyleDíaz-Gavela, Ana Aurora, Lourdes Figueiras-Graillet, Ángel Montero Luis, Juliana Salas Segura, Raquel Ciérvide, Elia del Cerro Peñalver, Felipe Couñago, Meritxell Arenas, and Teresa López-Fernández. 2021. "Breast Radiotherapy-Related Cardiotoxicity. When, How, Why. Risk Prevention and Control Strategies" Cancers 13, no. 7: 1712. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071712