Aimo A.

Gimelli A.

English

Archivio della ricerca della Scuola Superiore Sant'Anna

EDITORIALMyocardial perfusion years after radiationtherapy for left-sided breast cancer: Normalor abnormal? This is the questionAlberto Aimo, MD,a,b and Alessia Gimelli, MDca Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italyb Cardiology Division, University Hospital of Pisa, Pisa, Italyc Fondazione Toscana Gabriele Monasterio, Pisa, ItalyReceived Oct 31, 2019; accepted Oct 31, 2019doi:10.1007/s12350-019-01959-7See related article, https://doi.org/10.1007/s12350-019-01949-9.Breast cancer is the most commonly occurringcancer in women and the second most frequent canceroverall, with over 2 million new cases in 2018.1 Multipleadvances in screening, classification of tumors intobiologic subtypes, surgical techniques, and chemother-apy have contributed to earlier diagnosis of breastcancers and better management. Given the better prog-nosis of these patients, adverse effects from therapies,including those developing over long times, arebecoming increasingly important.2,3Treatment of breast cancer often consists in acombination of surgery, chemotherapy, and post-opera-tive adjuvant radiation therapy (RT) to the breast orchest wall, possibly extended to regional lymph nodes. Itis well known that both chemotherapy with anthracy-cline or trastuzumab and RT may be cause cardiactoxicity through different mechanisms, namely activa-tion of cell death pathways and inhibition ofmitochondrial biogenesis by anthracyclines,4 inhibitionof HER2 signaling in the heart by trastuzumab,5 andradiation-induced cardiac damage. This last can mani-fest as coronary artery atherosclerosis, cardiomyopathydue to microvascular dysfunction, and possibly alsopericarditis or valve disease.6 The risk of radiation-in-duced heart disease increases by about 7% per Gy ofmean absorbed dose; the goal of RT planning is then tokeep the dose to the heart as low as possible throughtarget-specific dose delivery (limiting cardiac irradiationto the anterior wall), and various heart-sparing tech-niques: respiratory gating to irradiate the breast regiononly during deep inspiration (when the heart is farthestfrom the chest wall), and 3D computed tomography(CT) planning to restrict cardiac irradiation to theanterior wall, perfused by the left anterior descending(LAD) artery.6 Since macro- or microvascular damagecan result in clinically manifest cardiac ischemia onlyover years or decades, and long follow-up periods arethen required, the impact of contemporary radiationprotocols remains to be determined. Impaired myocar-dial perfusion or coronary artery calcium score (CACS)may represent useful surrogate endpoints, denoting anearly damage that may become clinically evident overtime.Several studies reported myocardial perfusion defi-cits following RT for breast cancer, although they datedback to 1990s or 2000s, and employed single-photonemission computed tomography (SPECT) and cardiacmagnetic resonance (CMR) instead of the gold standardtechnique for in vivo quantification of myocardial bloodflow (MBF), namely positron emission tomogra-phy/computed tomography (PET/CT).7–16 In the onlystudy so far available, 15 women with breast cancer (9of whom with left-sided breast cancer) underwent rest-ing and adenosine PET/CT with the 15O-H2O tracerbefore RT (which was administered at 42.5 or 45.0 Gyover 17 or 20 sessions, respectively, plus an additionaldose for patients with intact breasts), and then 2 and8 months after completion of RT.17 A RT techniquerestricting irradiation to the anterior cardiac wall wasadopted. Accordingly, compared to baseline, restingmyocardial blood flow (MBF) was reduced at 2 and8 months only in the 7th left ventricular segment, andReprint requests: Alessia Gimelli, MD, Fondazione Toscana GabrieleMonasterio, Pisa, Italy; gimelli@ftgm.itJ Nucl Cardiol1071-3581/$34.00Copyright  2019 American Society of Nuclear Cardiology.reduced stress perfusion was mostly confined in theLAD territory. Changes in myocardial perfusion wereapparently not influenced by cancer side, age, cardio-vascular risk factors, or additional cancer therapies.17The study by Rasmussen et al, published in thepresent issue of the Journal, adds to our knowledge onthis topic.18 The authors evaluated 20 women receivingadjuvant RT (48 Gy over 24 sessions) for left-sidedbreast cancer, using a state-of-the-art RT technique.After 7 ± 2 years, patients underwent a 13N-NH3 PET/CT scan to assess CACS and myocardial perfusion. Themedian CACS was 4, and coronary calcifications wereprimarily located in the LAD territory. Resting MBF andmyocardial flow reserve (MFR) in the irradiated andnon-inferior zones did not differ significantly. Indeed,‘‘no differences were observed for rest MBF (1.29 ±0.29 vs 1.33 ± 0.29 mLg-1minute-1, P = ns), stressMBF (2.74 ± 0.59 vs 2.78 ± 0.66 mLg-1minute-1,P = ns), or MFR (2.22 ± 0.62 vs 2.17 ± 0.65, P = ns)between anterior and inferior wall myocardium.’’ Theauthors conclude that contemporary RT protocols do notseem to affect resting and stress myocardial perfusionafter several years from treatment.Although the authors correctly acknowledge mostlimitations of their analysis, we deem it useful to furtherdiscuss some points. First, the study population could betoo small for a small difference in myocardial perfusionto emerge. Indeed, the comparison between 20 irradiatedand 20 non-irradiated regions would have yielded asignificant difference (with 5% alpha error probabilityand 80% power) only if Cohen’s effect size was 0.42 (2-tail test) or 0.37 (1-tail test), over a scale from 0 to 1 (G-power software, version 3.1). In other words, a differ-ence in myocardial perfusion would have beendetectable only if irradiation was quite harmful to theheart, which is quite unlikely when using contemporaryRT protocols. The study was then probably underpow-ered to detect significant differences in myocardialperfusion between irradiated and non-irradiated zones.Other important limitations are the lack of baseline PET/CT imaging and the absence of a control group, whichcould have allowed a more meaningful assessment ofMBF and MFR values measured during follow-up. Onthe other hand, the finding of MBF and MFR values inthe irradiated region approaching reference values forhealthy women19 gives some support to the conclusionthat myocardial perfusion is not significantly altered byRT, at least over a 7-year timespan. Nonetheless, someRT-induced damage is suggested by an uneven distri-bution of calcifications, which were more represented inirradiated segments, and might represent the earliestevidence of vascular damage by RT. Overall, furtherstudies with longer follow-up periods are advisable toproperly investigate the consequences of RT oncoronary anatomy and myocardial perfusion. Thesestudies should also try to dissect the effects of RT fromthose of anthracyclines, which have been found to causeperfusion deficits in CMR studies.20In conclusion, Rasmussen et al should be congrat-ulated for addressing this topic of outmost clinicalrelevance, but their study should probably be regardedas hypothesis-generating rather than a clear demonstra-tion that myocardial perfusion is not reduced followingRT for left-sided breast cancer.DisclosureThe authors have indicated that they have no financialconflict of interest.References1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A.Global cancer statistics 2018: GLOBOCAN estimates of incidenceand mortality worldwide for 36 cancers in 185 countries. CACancer J Clin. 2018;68:394–424.2. Meattini I, Guenzi M, Fozza A, Vidali C, Rovea P, Meacci F, et al.Overview on cardiac, pulmonary and cutaneous toxicity in patientstreated with adjuvant radiotherapy for breast cancer. Breast Can-cer. 2017;24:52–62.3. Zhu Q, Kirova YM, Cao L, Arsene-Henry A, Chen J. Cardiotox-icity associated with radiotherapy in breast cancer: A question-based review with current literatures. Cancer Treat Rev.2018;68:9–15.4. Henriksen PA. Anthracycline cardiotoxicity: An update onmechanisms, monitoring and prevention. Heart. 2018;104:971–7.5. Mohan N, Jiang J, Dokmanovic M, Wu WJ. Trastuzumab-medi-ated cardiotoxicity: Current understanding, challenges, andfrontiers. Antib Ther. 2018;1:13–7.6. Spetz J, Moslehi J, Sarosiek K. Radiation-induced cardiovasculartoxicity: Mechanisms, prevention, and treatment. Curr TreatOptions Cardiovasc Med. 2018;20:31.7. Seddon B, Cook A, Gothard L, Salmon E, Latus K, UnderwoodSR, et al. Detection of defects in myocardial perfusion imaging inpatients with early breast cancer treated with radiotherapy.Radiother Oncol. 2002;64:53–63.8. Sioka C, Exarchopoulos T, Tasiou I, Tzima E, Fotou N, CapizzelloA, et al. Myocardial perfusion imaging with (99 m)Tc-tetrofosminSPECT in breast cancer patients that received postoperativeradiotherapy: A case-control study. Radiat Oncol. 2011;6:151.9. Gyenes G, Fornander T, Carlens P, Glas U, Rutqvist LE. Detectionof radiation-induced myocardial damage by technetium-99 msestamibi scintigraphy. Eur J Nucl Med. 1997;24:286–92.10. Hardenbergh PH, Munley MT, Bentel GC, Kedem R, Borges-NetoS, Hollis D, et al. Cardiac perfusion changes in patients treated forbreast cancer with radiation therapy and doxorubicin: Preliminaryresults. Int J Radiat Oncol Biol Phys. 2001;49:1023–8.11. Lind PA, Pagnanelli R, Marks LB, Borges-Neto S, Hu C, ZhouSM, et al. Myocardial perfusion changes in patients irradiated forleft-sided breast cancer and correlation with coronary artery dis-tribution. Int J Radiat Oncol Biol Phys. 2003;55:914–20.12. Marks LB, Yu X, Prosnitz RG, Zhou SM, Hardenbergh PH,Blazing M, et al. The incidence and functional consequences ofAimo and Gimelli Journal of Nuclear CardiologyMyocardial perfusion after radiation therapyRT-associated cardiac perfusion defects. Int J Radiat Oncol BiolPhys. 2005;63:214–23.13. Tzonevska A, Tzvetkov K, Parvanova V, Dimitrova M. 99mTc-MIBI myocardial perfusion scintigraphy for assessment ofmyocardial damage after radiotherapy in patients with breastcancer. J BUON. 2006;11:505–9.14. Prosnitz RG, Hubbs JL, Evans ES, Zhou SM, Yu X, Blazing MA,et al. Prospective assessment of radiotherapy-associated cardiactoxicity in breast cancer patients: Analysis of data 3 to 6 yearsafter treatment. Cancer. 2007;110:1840–50.15. Højris I, Sand NP, Andersen J, Rehling M, Overgaard M.Myocardial perfusion imaging in breast cancer patients treatedwith or without post-mastectomy radiotherapy. Radiother Oncol.2000;55:163–72.16. Jaarsma C, Leiner T, Bekkers SC, Crijns HJ, Wildberger JE, NagelE, et al. Diagnostic performance of noninvasive myocardial per-fusion imaging using single-photon emission computedtomography, cardiac magnetic resonance, and positron emissiontomography imaging for the detection of obstructive coronaryartery disease: A meta-analysis. J Am Coll Cardiol. 2012;59:1719–28.17. _Zyromska A, Małkowski B, Wiśniewski T, Majewska K, Reszke J,Makarewicz R. (15)O-H(2)O PET/CT as a tool for the quantitativeassessment of early post-radiotherapy changes of heart perfusionin breast carcinoma patients. Br J Radiol. 2018;91:20170653.18. Rasmussen T, Kjær A, Lassen M, Pedersen A, Specht L, Aznar M,et al. No changes in myocardial perfusion following radiationtherapy of left-sided breast cancer: A positron emission tomog-raphy study. J Nucl Cardiol. 2019. https://doi.org/10.1007/s12350-019-01949-9.19. Opstal TS, Knol RJ, Cornel JH, Wondergem M, van der Zant FM.Myocardial blood flow and myocardial flow reserve values in(13)N-ammonia myocardial perfusion PET/CT using a time-effi-cient protocol in patients without coronary artery disease. Eur JHybrid Imaging. 2018;2:11.20. Nguyen KL, Hu P, Ennis DB, Shao J, Pham KA, Chen JJ. CardiacMRI: A translational imaging tool for characterizing anthracy-cline-induced myocardial remodeling. Curr Oncol Rep.2016;18:48.Publisher’s Note Springer Nature remains neutral with regard tojurisdictional claims in published maps and institutional affiliations.Journal of Nuclear Cardiology Aimo and GimelliMyocardial perfusion after radiation therapy

Myocardial perfusion years after radiation therapy for left-sided breast cancer: Normal or abnormal? This is the question

https://www.iris.sssup.it/bitstream/11382/540908/1/document-16.pdf

Myocardial perfusion years after radiation therapy for left-sided breast cancer: Normal or abnormal? This is the question

Abstract

Similar works

Full text

Available Versions

Archivio della ricerca della Scuola Superiore Sant'Anna