CORONARY ARTERIES EXPOSURE IN LEFT SIDED BREAST CANCER RADIOTHERAPY : DOSIMETRIC STUDY

Purpose : The cardiac toxicities are especially important in left-sided breast cancer radiotherapy(RT) compared to the right-sidedcancers.Our study aims to perform a dosimetric analysis to evaluate the effect of RT on coronary arteries and heart in breast-conserving surgery. Methods : Through a dosimetric studywe randomly selected a total of 36 patients with early stage right and left-sided breast carcinomas (T1/T2 +N0) .All patients underwent breast-conserving surgery .Whole Breast Adjuvant Radiotherapy was delivered with tumor beds boost using 3D conformal radiotherapy (3D-CRT) and computed tomography based planning .The doses for coronary arteries and heart were recorded and median values compared between groups. Results : The highest mean of radiation dose in patients with left-sided breast cancer was to both left-sided than left-sided Did a study to describe hot-spotareas for radiation and classify RT as high or lowrisk  31  .In their study, the mean doses received bySwedish women treated for left-sided breast cancerin the 1990s were 3.0 ± 0.5 Gy to the heart and12.0 ± 2.3 Gy to the LAD (including 1 cm margin).These differences with the literaturecould be caused by differences in treatmenttechniques or more likely in contouring strategy: These results also indicate that a very low dose to LAD seems to be associated with a very low dose to the heart for breast tumors in different sides. To provideadditional information, we suggest that LAD should be contoured as a risk organ along with thewhole heart and used prospectively for optimization of RT plan. If it is not possible to contour bothstructures owing to limited time, the LAD should be preferred as an organ at risk.Handbook recommendation for breast RT is asfollows: LV and combined bilateral ventricle limits:V5 ≤ 10% and V25 ≤ 5%. The American Societyfor Radiation Oncology (ASTRO) ConsensusStatement dose constraints for 3D-CRT Accelerated Partial Breast Irradiation (IJROBP 2009) reports asfollows: heart V5 < 5% for right-sided tumors and< 40% for left-sided tumors  31  .. In this study ,the mean V5 of the LV was 20.32% (7.95–42.80). The mean V25 of the LV was 7.31% (0.91–18.34) and consistent with the recommendations. The mean V5 in the bilateral ventricles was 27.69% (4.64–29.81). The mean V25 in the bilateral ventricles was 8.72% (0.88–16.45). These limits were found higher than the recommendations, wich can increase the risk of cardiaccomplications. According to the guidelines, to minimize This study evaluated RT doses to the left anterior descending coronary artery (LAD),left circumflex coronary artery(LCx),right ventricle (RV), left ventricle (LV), and heart in patients who underwent right and left sided breast conservative surgery and determine whether these doses constituted a risk for ischemic heart disease.


107
generally associated with only weak or moderate elevations in risk. The exceptions occur in uncommon subgroups of these variables; for example, a family history of breast cancer at a young age or a family history of bilateral disease3-4.
Adjuvant breast irradiation after breast-conserving surgery leads to similar oncological outcomes as mastectomy (radical mastectomy, modified radical mastectomy,or total mastectomy) in patients with early breast cancer and improves survival in comparison to breast-conserving surgery alone (wide excision, quadrantectomy, or lumpectomy)5-6.Adjuvant RT,especially for left-sided breast cancer was associated with cardiotoxixity and cardiovascular mortality when compared to patients treated with surgery alone7in particular, the left anterior descending coronary artery (LAD) receives significant radiation, being in ornear the target volume8-9.

Patients and Methods:-Patients
This is a dosimetric study, that included 38 patientswith early stage right and left-sided breast cancer (T1/T2 + N0, accordingto-8th edition of American Joint Committeeon Cancer staging, 2017)from December 2018 to February 2021 for this dosimetric study .They had undergone breast conserving surgery.RT was delivered to the whole breast,and tumor beds were boosted using 3D-CRT with tangential fields and computed tomography (CT) based planning.Patient's age tumor localization,stage,chemotherapy protocol and number,Radiotherapy dose and doses for coronary arteries : LAD, LCx,RV, LV and heart were recorded and summarized below Table 1. All patients agreed to the conditions of this study. We based on handbook and quantec to dose limits for critical organs. Handbook recommendations for breast RT is as follows: LVand combined bilateral ventricle limits: V5 ≤ 10 %and V25 ≤ 5 %. Controlateral breast Dmax ≤ 3%,ipsilateral lung V30 < 15%,contralateral lung V5 < 15%, heart V5 < 5% for R-sided tumors, and < 40% for L-sided tumors.

Treatment and Planning
All patients included in this study underwent RT for right and left-sided breast cancers at the Cheikh Khalifa International Hospital in the Radiation Oncology Departement.They had undergone breast-conserving surgery followed by Adjuvant Radiotherapy.Contrast-enhanced CT scans were obtained in 3mm slices as a part of radiation planning. During simulation, each patient was immobilized, with the ipsilateral arm above her head. Radiopaque catheters were placed to delineate the breast areas and incision scar on the CT scan. Each patient's CT data was transferred to an in-house 3-dimensional treatment planning system (TPS).The Clinical Target Volumes(CTVs) were contoured by radiation oncologist.The breast CTV included the whole breast with 5mm retraction from the skin surface.The planning Target Volume(PTV) comprised the CTV with a 7mm circumferential margin to allow for daily set-up variations and account for setup uncertainties and respiratory motion,and was also retracted 5mm from the skin surface.
The involved OARs including contra-lateral breast ,entire heart ,left and right lung, LAD, LCx, RV, LV,spinal cord , oesophagus and liver were delineated by the treating physician .For RT planing two tangential beams were used with a matched posterior border to avoid divergence.The total dose prescribed was 60Gy,with 2.0 Gy per fraction per day (50 Gy in 2 Gy/fraction in 25 fractions to whole breast, 10 Gy in 2 Gy/5 fractions to tumor bed) according to the ICRU report number 8310-11.
The aim of the treatment plan was to achieve at least 95% of the planning target volume receiving 47.5 Gy (95% of 50.0 Gy), and the ipsilateral lung volume receiving 20 Gy or more (V20) _ 10%, while keeping the contralateral lung below a mean dose of 5 Gy. In allpatients, Varian linear accelarator fitted with Multi Leaf Collimator (MLCi) was used totreatthe breast with 6-MV photon energy beam.The boost was applied with electronsenergy. Electron energy was selected to allow the 85-90% isodose line to encompasstarget. Dose volume histograms (DVH) were reviewed for all the patients. Maximum, minimum, and mean doses (Dmax, Dmin, and Dmean) to heart, LAD, LCx, RV, and LV were calculated from the cumulative Histogram Dose Volume (DVH).

Analysis statistics
Both analyses and results were performed using JAMOVI Statistical Software,online version, and a statistical significance level of 0.05 was used (p<0.05). 108

Results:-
A total of 38 patients were included in our study ;all of them had undergone breast conserving surgery followed by adjuvant RT.We divided them into two equal groups .Nineteen patients had right-sided breast cancer and nineteen had a left-sided one.
The doses calculated after RT planning in patientswith right and left sided breast cancer arepresented below Table 2. All Dmean, Dmax and Dminvalues on LAD, LCx, RV, LV and heart of the patientswith left-sided breast cancer were significantlyhigher than the values of the patients withright-sided cancer (P < 0.0001).The mean V5 of the LV was 20.32% (7.95-42.80).The mean V25 of the LV was 7.31% (0.91-18.34). The mean V5 in the bilateral ventricles was 27.69% (4.64-29.81). The mean V25 in the bilateral ventricles was 8.72% (0.88-16.45).

Discussion:-
Breast cancer is the primary cause of cancer mortality after lung cancer and the most commoncancer among women .A number of randomized controlled clinical trials have shown that breast conserving surgery combined with postoperative radiation therapy(PORT) has the same curative effect as theHalsted radical mastectomy. Port has been shown improvement of long-term survival and significant reduction of local relapse but in the other hand major toxicities to the organs at risk(OARs) : heart,the lung and a risk of secondary breast cancer were found 12-13. Latest update for Early BreastCancerTrial Writers Cooperation Group demonstrates radiation therapy was associated with excessive cardiac mortality disease. However, many of the studies included in a review involved older treatmenttechniques, which probably delivered a higher dose to the heart than seen in modern radiotherapy clinics .Thecardiovascular complications induced by radiation as a main radiotherapy-related late toxicity14. This is a new concern since new research suggest that arteries are particularly susceptibleto radiation.The injury of coronary artery induced by radiation is consistent with coronary atherosclerosisdue to additional factors 15-16. Clinical studies have demonstrated that the incidence of coronary artery disease in patients is up to 85%, it closely related to the radiation dose, location, time, and other factors17-18-19.In our study, we used the regimensthat were routinely used in breast cancer patientsand determined our cardiac dose rates, accordingto the dose and plan used forright and left-sidebreast RT, and tried to evaluate the effect of thesedoses on coronary disease risk.Aznar MC et al.In their study19,included womenin the age ranging from 36 to 76 years, with medianage 58.5 years, at the time of treatment.Chung etal,in their study, included women with a medianage of 50 (25-74) years. In our study,the mean age of the patients with right-sided breast cancerwas 52 (37-76) years and of those with the left-sided breast cancer was 55 (40-72) years.In the last decade it has been a strong focus on reducing the radiation dose to the heart in order to minimise the risk of side effects with the help of advanced imaging and treatment techniques20.The highest radiation doses are likely to be the anterior portion of the heart ,including the left anterior descending coronary artery(LAD) especially in left-sided breast RT .This is a concern since new studies suggest those arteries are particularly sensitive to radiation and the cardiovascular mortality tends to increase after RT21-22.According to the Quantitative Analyses ofNormal Tissue Effects in the Institution, NationalSurgical Adjuvant Breast and Bowel Project, andRadiation Therapy Oncology protocols,heartmean dose is < 26 Gy, < 4 Gy, and < 32 Gy, respectively.In our study, the cardiac morbidity or the cardiovascular mortality was not examined since it was nota follow-up study.The RACE collaboration reported a doseresponserelationship between the heartsdiseaserisk and mean dose 23.Compared withthe women with estimated heart doses <5 Gy, therelative risks of heart disease in women with estimateddoses 5 to 14 Gy and > 15 Gy were 15%and 108% higher, respectively. The Danish Breast CancerCooperative Group recommends that the volumeof heart receiving more than 40 Gy be kept below5%, as well as the volume receiving more than 20Gy be kept under 10%.Although it is generallyaccepted that a dose of 40 Gy or more of radiationcan lead to heart disease, McGale and Darby haveshown evidence of an increased risk of 109 radiationinducedheart disease at doses below 5 Gy24-25.In ourstudy, the mean doses for heart of patients with a left-sided breast cancer was 4.80 ± 1.23 Gy, andthe maximum dose was 50.45 ± 2.96 Gy. For hearts ofpatients with a right-sided breast cancer, the mean of dose was 2.03 ± 0.45 Gy, and maximum dose was 7.49 ± 8.61 Gy, suggesting a reasonable estimatedlower dose on heart compared with the heart of patientswith left-sided breast cancer for the relativerisk of heart. To adequately predict the cardiac risks of modern radiation techniques,the determination of a relationship between cardiac doses and long-term morbidity and mortality isnecessary26-27.In our study , the long-term effects of RT and heart disorders should be investigated in future .Hooning et al., retrospectively reviewedthe incidence of cardiovascular diseasein10-year survivors of breast cancer, treated from 1970 through 198628-29.Although the risk ofcardiovasculardisease increased with increasing estimated mean heart doses, the risk was decreasedwith more modern treatment techniques. More recently, Nilsson et al.Demonstrated with the coronaryangiography that the location and severity of coronary artery stenosis correlates with the expectedregions of high-dose radiation, especially for left-sided radiation or inclusion of the internal mammarynodes28.Correa et al, conducted a study on14 patients, 13 with left and one with right-sidedbreast cancer, wich had stress tests and underwentcardiac catheterization. In this study, in 11 of the 13patients, the LAD was affected. In eight of these 11 patients,a single vessel was affected, in one patient,both LADs and the LCx were diseased, and in oneother patient, three main coronary vessels werediseased. On the other hand, 1 patient had LCx and right coronary stenosis without evidence ofLAD disease30.In our study, not only the mean andmaximum doses of RT on heart of left-sided breastcancer were higher than the right-sided cancer, but also the mean, maximum and minimum doses onLAD, LCx, and both ventricles of left-sided cancer were also significantly higher than leftsided cancers,suggesting a possibility of tendency for heart diseases as well as LAD and LCx diseases.Taylor et al. Did a study to describe hot-spotareas for radiation and classify RT as high or lowrisk31.In their study, the mean doses received bySwedish women treated for left-sided breast cancerin the 1990s were 3.0 ± 0.5 Gy to the heart and12.0 ± 2.3 Gy to the LAD (including 1 cm margin).These differences with the literaturecould be caused by differences in treatmenttechniques or more likely in contouring strategy: These results also indicate that a very low dose to LAD seems to be associated with a very low dose to the heart for breast tumors in different sides. To provideadditional information, we suggest that LAD should be contoured as a risk organ along with thewhole heart and used prospectively for optimization of RT plan. If it is not possible to contour bothstructures owing to limited time, the LAD should be preferred as an organ at risk.Handbook recommendation for breast RT is asfollows: LV and combined bilateral ventricle limits:V5 ≤ 10% and V25 ≤ 5%. The American Societyfor Radiation Oncology (ASTRO) ConsensusStatement dose constraints for 3D-CRT Accelerated Partial Breast Irradiation (IJROBP 2009) reports asfollows: heart V5 < 5% for right-sided tumors and< 40% for left-sided tumors31.. In this study ,the mean V5 of the LV was 20.32% (7.95-42.80). The mean V25 of the LV was 7.31% (0.91-18.34) and consistent with the recommendations. The mean V5 in the bilateral ventricles was 27.69% (4.64-29.81). The mean V25 in the bilateral ventricles was 8.72% (0.88-16.45). These limits were found higher than the recommendations, wich can increase the risk of cardiaccomplications. According to the guidelines, to minimize cardiacside effects, the left ventricular dose shouldbe V5 ≤ 10%, the bilateral ventricular dose V25 ≤5%, and the whole heart dose < 4 Gy. For this purpose, a study reported that deep inspiration breath holdplans proved large reductions of dose to the heart.V20 of the heart is reduced from 7.8% to 2.3%, V40from 3.4% to 0.3% and mean dose from 5.2 to 2.7Gy32.This technique (deep inspiration breath hold respiratory gating) may be used to minimize dose to heart .Our estimates will be useful to improve radiotherapy practice and to better management of radiation-related heart diseases.

Conclusion:-
Adjuvant radiotherapy for breast cancer patients can lead to cardiac morbidity and mortality aftertreatment due to excessive heart irradiation . In our experience we suggest that the whole heartsubstructures and especially the LAD in the left-sided breast cancers must be contoured with precision as organ at risks , if necessary, deep inspiration breath hold respiratory gating and modern techniques are highly recommended to reduce radiation-related heart diseases.

What is already known on this Topic
Multiple follow-up studies have shown that delivery of radiation breast or chest-wall results in delayed cardiac morbidities ranging fromischemic heart disease (IHD) to acute coronary syndromes and finally congestive cardiacfailure. 110