Subclinical Left Ventricular Dysfunction Detected by Speckle-Tracking Echocardiography in Breast Cancer Patients Treated With Radiation Therapy: A Six-Month Follow-Up Analysis (MEDIRAD EARLY-HEART study)

Médéa Locquet, Daan Spoor, Anne Crijns, Pim van der Harst, Arantxa Eraso, Ferran Guedea, Manuela Fiuza, Susana Constantino Rosa Santos, Stephanie Combs, Kai Borm, Elie Mousseaux, Umit Gencer, Guy Frija, Elisabeth Cardis, Hans Langendijk, Sophie Jacob, Médéa Locquet, Daan Spoor, Anne Crijns, Pim van der Harst, Arantxa Eraso, Ferran Guedea, Manuela Fiuza, Susana Constantino Rosa Santos, Stephanie Combs, Kai Borm, Elie Mousseaux, Umit Gencer, Guy Frija, Elisabeth Cardis, Hans Langendijk, Sophie Jacob

Abstract

Background: In the case of breast cancer (BC), radiotherapy (RT) helps reduce locoregional recurrence and BC-related deaths but can lead to cardiotoxicity, resulting in an increased risk of long-term major cardiovascular events. It is therefore of primary importance to early detect subclinical left ventricular (LV) dysfunction in BC patients after RT and to determine the dose-response relationships between cardiac doses and these events.

Methods: Within the frame of the MEDIRAD European project (2017-2022), the prospective multicenter EARLY-HEART study (ClinicalTrials.gov Identifier: NCT03297346) included chemotherapy naïve BC women aged 40-75 years and treated with lumpectomy and adjuvant RT. Myocardial strain analysis was provided using speckle-tracking echocardiography performed at baseline and 6 months following RT. A global longitudinal strain (GLS) reduction >15% between baseline and follow-up was defined as a GLS-based subclinical LV dysfunction. Individual patient dose distributions were obtained using multi-atlas-based auto-segmentation of the heart. Dose-volume parameters were studied for the whole heart (WH) and left ventricle (LV).

Results: The sample included 186 BC women (57.5 ± 7.9 years, 64% left-sided BC). GLS-based subclinical LV dysfunction was observed in 22 patients (14.4%). These patients had significantly higher cardiac exposure regarding WH and LV doses compared to patients without LV dysfunction (for mean WH dose: 2.66 ± 1.75 Gy versus 1.64 ± 0.96 Gy, p = 0.01). A significantly increased risk of subclinical LV dysfunction was observed with the increase in the dose received to the WH [ORs from 1.13 (V5) to 1.74 (Dmean); p <0.01] and to the LV [ORs from 1.10 (V5) to 1.46 (Dmean); p <0.01]. Based on ROC analysis, the LV-V5 parameter may be the best predictor of the short-term onset of subclinical LV dysfunction.

Conclusion: These results highlighted that all cardiac doses were strongly associated with the occurrence of subclinical LV dysfunction arising 6 months after BC RT. Whether measurements of GLS at baseline and 6 months after RT combined with cardiac doses can early predict efficiently subclinical events occurring 24 months after RT remains to be investigated.

Keywords: EARLY-HEART cohort; MEDIRAD; breast cancer; cardiac dysfunction; dosimetry; radiotherapy; strain imaging.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Locquet, Spoor, Crijns, van der Harst, Eraso, Guedea, Fiuza, Santos, Combs, Borm, Mousseaux, Gencer, Frija, Cardis, Langendijk and Jacob.

Figures

Figure 1
Figure 1
Flowchart of BC patient inclusion and exclusion in the EARLY-HEART study based on echocardiography.
Figure 2
Figure 2
Comparisons of dose-volume parameters between BC patients with or without a reduction of GLS >15%; Dmean to WH (A) and LV (B) (Gy), V5 of WH (C) and LV (D), and V20 of WH (E) and LV (F); mean values: numerical and ♦.

References

    1. Kelsey JL. A Review of the Epidemiology of Human Breast Cancer. Epidemiol Rev (1979) 1:74–109. doi: 10.1093/OXFORDJOURNALS.EPIREV.A036215
    1. McGale P, Taylor C, Correa C, Cutter D, Duane F, Ewertz M, et al. . Effect of Radiotherapy After Mastectomy and Axillary Surgery on 10-Year Recurrence and 20-Year Breast Cancer Mortality: Meta-Analysis of Individual Patient Data for 8135 Women in 22 Randomised Trials. Lancet (London England) (2014) 383:2127–35. doi: 10.1016/S0140-6736(14)60488-8
    1. Cheng YJ, Nie XY, Ji CC, Lin XX, Liu LJ, Chen XM, et al. . Long-Term Cardiovascular Risk After Radiotherapy in Women With Breast Cancer. J Am Heart Assoc (2017) 6:1–14. doi: 10.1161/JAHA.117.005633
    1. Sardar P, Kundu A, Chatterjee S, Nohria A, Nairooz R, Bangalore S, et al. . Long-Term Cardiovascular Mortality After Radiotherapy for Breast Cancer: A Systematic Review and Meta-Analysis. Clin Cardiol (2017) 40:73. doi: 10.1002/CLC.22631
    1. Gagliardi G, Constine LS, Moiseenko V, Correa C, Pierce LJ, Allen AM, et al. . Radiation Dose-Volume Effects in the Heart. Int J Radiat Oncol Biol Phys (2010) 76:S77–85. doi: 10.1016/J.IJROBP.2009.04.093
    1. Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Brønnum D, et al. . Risk of Ischemic Heart Disease in Women After Radiotherapy for Breast Cancer. N Engl J Med (2013) 368:987–98. doi: 10.1056/NEJMOA1209825
    1. Van Den Bogaard VAB, Ta BDP, van der Schaaf A, Bouma AB, Middag AMH, Bantema-Joppe EJ, et al. . Validation and Modification of a Prediction Model for Acute Cardiac Events in Patients With Breast Cancer Treated With Radiotherapy Based on Three-Dimensional Dose Distributions to Cardiac Substructures. J Clin Oncol (2017) 35:1171. doi: 10.1200/JCO.2016.69.8480
    1. Taylor C, Duane FK, Dodwell D, Gray R, Wang Z, Wang Y, 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. doi: 10.1200/JCO.2016.72.0722
    1. Belzile-Dugas E, Eisenberg MJ. Radiation-Induced Cardiovascular Disease: Review of an Underrecognized Pathology. J Am Heart Assoc (2021) 10:1–10. doi: 10.1161/JAHA.121.021686
    1. Luis Zamorano J, Lancellotti P, Rodriguez Muñ oz D, Aboyans V, Asteggiano R, Galderisi M, et al. . 2016 ESC Position Paper on Cancer Treatments and Cardiovascular Toxicity Developed Under the Auspices of the ESC Committee for Practice Guidelines The Task Force for Cancer Treatments and Cardiovascular Toxicity of the European Society of Cardiology (ESC). Eur Heart J. (2016) 37(36):2768–2801. doi: 10.1093/eurheartj/ehw211
    1. Lang RM, Badano LP, Victor MA, Afilalo J, Armstrong A, Ernande L, et al. . Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update From the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr (2015) 28:1–39.e14. doi: 10.1016/J.ECHO.2014.10.003
    1. Kalam K, Otahal P, Marwick TH. Prognostic Implications of Global LV Dysfunction: A Systematic Review and Meta-Analysis of Global Longitudinal Strain and Ejection Fraction. Heart (2014) 100:1673–80. doi: 10.1136/HEARTJNL-2014-305538
    1. Guerra F, Marchesini M, Contadini D, Menditto A, Morelli M, Piccolo E, et al. . Speckle-Tracking Global Longitudinal Strain as an Early Predictor of Cardiotoxicity in Breast Carcinoma. Support Care Cancer (2016) 24:3139–45. doi: 10.1007/S00520-016-3137-Y
    1. Walker V, Lairez O, Fondard O, Pathak A, Pinel B, Chevelle C, et al. . Early Detection of Subclinical Left Ventricular Dysfunction After Breast Cancer Radiation Therapy Using Speckle-Tracking Echocardiography: Association Between Cardiac Exposure and Longitudinal Strain Reduction (BACCARAT Study). Radiat Oncol (2019) 14:204. doi: 10.1186/S13014-019-1408-8
    1. Tuohinen SS, Skyttä T, Poutanen T, Huhtala H, Virtanen V, Kellokumpu-Lehtinen PL, et al. . Radiotherapy-Induced Global and Regional Differences in Early-Stage Left-Sided Versus Right-Sided Breast Cancer Patients: Speckle Tracking Echocardiography Study. Int J Cardiovasc Imaging (2017) 33:463–72. doi: 10.1007/S10554-016-1021-Y
    1. Trivedi SJ, Choudhary P, Lo Q, Sritharan HP, Iyer A, Batumalai V, et al. . Persistent Reduction in Global Longitudinal Strain in the Longer Term After Radiation Therapy in Patients With Breast Cancer. Radiother Oncol (2019) 132:148–54. doi: 10.1016/J.RADONC.2018.10.023
    1. Erven K, Jurcut R, Weltens C, Giusca S, Ector J, Wildiers H, et al. . Acute Radiation Effects on Cardiac Function Detected by Strain Rate Imaging in Breast Cancer Patients. Int J Radiat Oncol Biol Phys (2011) 79:1444–51. doi: 10.1016/J.IJROBP.2010.01.004
    1. Negishi K, Negishi T, Hare JL, Haluska BA, Plana JC, Marwick TH. Independent and Incremental Value of Deformation Indices for Prediction of Trastuzumab-Induced Cardiotoxicity. J Am Soc Echocardiogr (2013) 26:493–8. doi: 10.1016/J.ECHO.2013.02.008
    1. Jacob S, Pathak A, Franck D, Latorzeff I, Jimenez G, Fondard O, et al. . Early Detection and Prediction of Cardiotoxicity After Radiation Therapy for Breast Cancer: The BACCARAT Prospective Cohort Study. Radiat Oncol (2016) 11:54. doi: 10.1186/S13014-016-0627-5
    1. Walker V, Crijns A, Langendijk J, Spoor D, Vliegenthart R, Combs SE, et al. . Early Detection of Cardiovascular Changes After Radiotherapy for Breast Cancer: Protocol for a European Multicenter Prospective Cohort Study (MEDIRAD EARLY HEART Study). JMIR Res Protoc (2018) 7(10):e178. doi: 10.2196/RESPROT.9906
    1. Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies. PloS Med (2007) 4:1623–7. doi: 10.1371/JOURNAL.PMED.0040296
    1. Spoor DS, Sijtsema NM, van den Bogaard VAB, van der Schaaf A, Brouwer CL, Ta BDP, et al. . Validation of Separate Multi-Atlases for Auto Segmentation of Cardiac Substructures in CT-Scans Acquired in Deep Inspiration Breath Hold and Free Breathing. Radiother Oncol (2021) 163:46–54. doi: 10.1016/J.RADONC.2021.07.025
    1. Tuohinen SS, Skyttä T, Huhtala H, Poutanen T, Virtanen V, Kellokumpu-Lehtinen PL, et al. . 3-Year Follow-Up of Radiation-Associated Changes in Diastolic Function by Speckle Tracking Echocardiography. JACC CardioOncology (2021) 3:277–89. doi: 10.1016/J.JACCAO.2021.03.005
    1. Dandel M, Lehmkuhl H, Knosalla C, Suramelashvili N, Hetzer R. Strain and Strain Rate Imaging by Echocardiography – Basic Concepts and Clinical Applicability. Curr Cardiol Rev (2009) 5:133. doi: 10.2174/157340309788166642
    1. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF, Dokainish H, Edvardsen T, et al. . Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update From the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr (2016) 29:277–314. doi: 10.1016/J.ECHO.2016.01.011
    1. Altiok E, Neizel M, Tiemann S, Krass V, Becker M, Zwicker C, et al. . Layer-Specific Analysis of Myocardial Deformation for Assessment of Infarct Transmurality: Comparison of Strain-Encoded Cardiovascular Magnetic Resonance With 2D Speckle Tracking Echocardiography. Eur Hear J Cardiovasc Imaging (2013) 14:570–8. doi: 10.1093/EHJCI/JES229
    1. Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie M, et al. . Expert Consensus for Multimodality Imaging Evaluation of Adult Patients During and After Cancer Therapy: A Report From the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging (2014) 15:1063–93. doi: 10.1093/EHJCI/JEU192
    1. Park SH, Goo JM, Jo CH. Receiver Operating Characteristic (ROC) Curve: Practical Review for Radiologists. Korean J Radiol (2004) 5:11–8. doi: 10.3348/KJR.2004.5.1.11
    1. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the Areas Under Two or More Correlated Receiver Operating Characteristic Curves: A Nonparametric Approach. Biometrics (1988) 44:837. doi: 10.2307/2531595
    1. Fourati N, Charfeddine S, Chaffai I, Dhouib F, Farhat L, Boukhris M, et al. . Subclinical Left Ventricle Impairment Following Breast Cancer Radiotherapy: Is There an Association Between Segmental Doses and Segmental Strain Dysfunction? Int J Cardiol (2021) 345:130–6. doi: 10.1016/J.IJCARD.2021.10.026
    1. Jacob S, Camilleri J, Derreumaux S, Walker V, Lairez O, Lapeyre M, et al. . Is Mean Heart Dose a Relevant Surrogate Parameter of Left Ventricle and Coronary Arteries Exposure During Breast Cancer Radiotherapy: A Dosimetric Evaluation Based on Individually-Determined Radiation Dose (BACCARAT Study). Radiat Oncol (2019) 14:29. doi: 10.1186/S13014-019-1234-Z
    1. Farsalinos KE, Daraban AM, Ünlü S, Thomas JD, Badano LP, Voigt JU. Head-To-Head Comparison of Global Longitudinal Strain Measurements Among Nine Different Vendors: The EACVI/ASE Inter-Vendor Comparison Study. J Am Soc Echocardiogr (2015) 28:1171–81.e2. doi: 10.1016/J.ECHO.2015.06.011

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다