adjuvant radiotherapy after breast - conserving surgery constitutes an indispensable part of breast conserving therapy in early breast cancer . the standard technique of radiation therapy is to treat the entire breast up to a total dose of 40 - 50 gy , with or without a boost dose of 10 - 15 gy to the tumor bed depending on boost indications . a decreased risk of local recurrence , particularly in younger patients , as a result of a boost dose has been confirmed in a large randomized trial . for selected low - risk patients , accelerated partial breast irradiation ( apbi ) is an alternative treatment option to whole - breast radiotherapy ( wbrt ) . a non - inferiority of apbi with interstitial multi - catheter brachytherapy ( bt ) technique was recently proved by gec - estro ( groupe europen de curiethrapie european society for radiotherapy and oncology ) trial . brachytherapy is an attractive option for both tumor - bed boost and apbi , allowing local dose escalation while reducing the dose to the surrounding normal structures . radiotherapy for breast cancer often involves some incidental exposure of the heart to ionizing radiation . darby et al . demonstrated that the relative risk of major cardiac events including myocardial infarction , coronary revascularization , and death from ischemic heart disease , increases linearly with the mean heart dose ( mhd ) by 7.4% per gray with no apparent threshold . the increase of the subsequent rate of ischemic heart disease in irradiated patients is proportional to mhd , begins within a few years after exposure , and continues for at least 20 years . apart from individual characteristics i.e. co - morbidities and age , systemic therapy such as anthracyclines and trastuzumab may further potentiate the radiation s effect on the heart . the aim of this study was to assess dose received by the left anterior descending ( lad ) coronary artery during interstitial multi - catheter pulsed - dose - rate bt ( pdr - bt ) boost with 3-dimensional ( 3d ) computed tomography ( ct ) based planning for left - sided breast cancer patients undergoing organ - sparing treatment . thirty consecutive patients were selected from women who received interstitial multi - catheter 3d pdr - bt boost dose to the conserved left breast , following wbrt at the medical university of gdask between 2014 - 2015 ( table 1 ) . catheter implantation was performed in a geometrically uniform way using the standardized templates for a triangular array with 16 mm separation of the holes . post - implant , non - contrast ct with a slice thickness of 3 mm was done . the contours of ptv ( planning target volume ) and critical organs ( skin and ribs ) were imported and analyzed in treatment planning system oncentra v. 3.3 ( nucletron , an elekta company , elekta ab , stockholm , sweden ) . the clinical target volume ( ctv ) consisted of the tumor bed with an adequate safety margin . the size of the safety margin was calculated as the sum of the width of the clear pathological surgical margins , and the radiation safety margin based on the localization of the clips left in tumor bed . it had to be approximately 20 mm , as defined individually for every patient , considering clinical information . the ptv was contoured 5 mm below the skin and above the chest wall , or just above the chest wall along the pectoralis muscle for superficial and deep tumors , respectively . paris system rules , with graphical and manual optimization to deliver adapted homogenous dose distribution to the ptv , and to keep the dose non - uniformity ratio ( v150/v100 ; dnr ) as close as recommended ( < 0.35 ) were applied . dose - volume histogram analyses were used to confirm that 100% of the prescribed dose covered at least 90% of the target volume . the maximum skin dose was restricted to less than 100% of the prescribed dose . a dose of 10 gy with pulses of 1 gy / h was delivered . patient and tumor characteristics ( n = 30 ) wbrt  whole breast radiotherapy , 3d - tcrt 3-dimensional tangential conformal radiotherapy the lad was retrospectively contoured on the ct scans by one of the radiation oncologists , based on guidelines described by the feng et al . . left anterior descending coronary artery was contoured from its origin to each utmost visible part on planning ct image ( figure 1 ) . a margin of 5 mm was added to each lad ( lad5 mm ) to allow for uncertainties regarding the exact position of the coronary artery . dosimetric parameters extracted from dose - volume histograms including lad doses of standardized plans were analyzed . rigid needles , planning target volume , and organs at risk including left anterior descending ( lad ) coronary artery ( a ) , and isodose 10% of the prescribed dose with reference to lad ( b ) statistical analysis was performed using spss software ( version 20.0 , ibm corporation , usa ) . for statistical analyses , four quadrants of the breast were assumed . if > 50% of the ptv was situated above the line dividing the breast into equal upper and lower portions , than the location was assigned as dose distribution to lad , according to the tumor bed localization was compared by u - mann whitney test with two - sided p - values and significance level of  = 0.05 . statistical analysis was performed using spss software ( version 20.0 , ibm corporation , usa ) . quantitative data were expressed as mean  standard deviation ( sd ) . for statistical analyses , four quadrants of the breast were assumed . if > 50% of the ptv was situated above the line dividing the breast into equal upper and lower portions , than the location was assigned as  upper  . dose distribution to lad , according to the tumor bed localization was compared by u - mann whitney test with two - sided p - values and significance level of  = 0.05 . selected parameters of bt implants are presented in table 2 . the volume enclosed by the reference isodose ranged from 15.3 cc to 109.3 cc ( mean 42 cc ) tumor bed was in upper quadrants in 80% of cases , with the upper inner quadrant being the most common localization . unsatisfactory higher dnr in half of the cases was related to our learning curve in 3d planning . a summary of radiation doses to the lad and lad5 mm including d0.1cc ( representing the highest dose received by 0.1 cc of the lad , i.e. the dose peak ) is presented in table 3 . the average ( dmean ) and maximal dose ( dmax ) to lad were 1 gy and 1.57 gy , respectively . there is substantial patient - to - patient variability with the lad dmax up to 55% of the prescribed dose . d0.1cc of the lad and lad5 mm were 1.42 gy and 1.85 gy ( range : 0.01 - 4.98 gy and 0.1 - 6.89 gy , respectively ) . dose distribution to lad according to the tumor bed localization is presented in table 4 . there was no difference in dmax to lad for medial versus lateral parts of the breast ( p = 0.92 ) . no differences were noted for average dose according to tumor bed location ( lower vs. upper quadrants ; p = 0.35 , medial vs. lateral quadrants ; p = 0.92 ) . dmax to lad was significantly higher for tumors located in lower versus upper part of the breast ( p = 0.04 ) . selected parameters of brachytherapy implants ( 10 gy in 10 pulses per hour , n = 30 ) dnr  dose non - uniformity ratio , v100  the percentage of the planning target volume ( ptv ) receiving 100% of the prescribed dose or more , d90  the percentage of the prescribed dose received by 90% volume of the ptv radiation dose to left anterior descending ( lad ) coronary artery for 30 left - sided breast cancer patients treated with 10 gy/10 pulses / hour pulsed - dose - rate brachytherapy tumor - bed boost lad  left anterior descending coronary artery dose distribution to left anterior descending ( lad ) coronary artery according to the tumor bed localization lad  left anterior descending coronary artery micro- and macro - vascular injury in tissues within the radiotherapy field is considered the main pathophysiological cause of radiation - related heart disease . the lad artery is of particular interest by its anatomical localization within the high dose region ( denoted by 95% of the radiation prescription ) of the wbrt fields . an increased risk of stenosis in the lad for left - sided radiotherapy ( rt ) was reported . according to darby et al . , a study based on doses estimated from the rt charts , the mhd was a better predictor of the rate of major coronary events ( angina episodes were not included ) than the mean dose to the lad . in clinical practice , several reports evaluated heart dose during breast irradiation and have provided ( for standard fractionation ) current recommendations of mhd and dose and volume constrains for this organ - at - risk ( oar ) to keep the probability of long - term cardiac mortality < 1% [ 8 , 9 , 10 , 11 ] . more recently , danish experts have suggested to respect dose constrains to the heart as well as maximal dose to lad of 20 gy . in the literature , there are limited data of lad doses during breast irradiation , with only two published reports considering multi - catheter high - dose - rate bt ( hdr - bt ) as a form of apbi [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ] ( table 5 ) . chan et al .   performed a quantitative intra - patient comparison of oar dosimetry between hdr - bt versus wbrt in a group of 15 patients with left breast cancer . the authors assumed the maximum dose for the heart as a parameter to report lad dose . the mean lad dose was 6.0 gy , which constitutes 17.6% of the prescribed bt dose of 34 gy in 10 twice daily fractions , and 5.9% ( after adjusting for eqd2 ) of 50 gy . accelerated partial breast irradiation with the use of hdr - bt compared to conformal wbrt was associated with a significant reduction in radiation dose for the lad ( dmean 6.0 gy vs. 45.9 gy ; p < 0.01 ; dose differed by a factor of 7.7 ) . the lad dose was the highest ( 7.8 gy ) in lower inner quadrant - located tumors . in this study , the d0.1cc of the heart and the mhd were 16.3 gy and 2.3 gy for apbi , respectively , and were significantly lower than for wbrt . study , which compared radiation dose to the lad during hdr - bt apbi and wbrt , lad was outlined as in our series , but in uncertain bt cases each artery was identified with reference to the preoperative enhanced ct images to determine lad . in the bt group ( 100 cases ) , mean ptv was 35.8 cc ( 6.8 - 135.8 ) , mean v100 29.8 cc ( 7.0 - 106.5 ) , and mean dnr was 0.3 ( 0.2 - 0.6 ) . the mean number of catheters and implant planes was 6.1 ( 3 - 12 ) and 1.6 ( 1 - 3 ) , respectively . in this series , the mean and maximal lad doses for tumors in inner quadrants or central locations ( 2.54  0.21 and 4.43  0.38 gy , respectively ) were significantly higher than those in outer quadrants ( 1.02  0.17 and 2.1  0.29 gy , respectively ; p < 0.0001 ) . after adjustment of the cumulative lad dose of apbi to wbrt using the bed equations , the mean and maximal doses in bt patients were significantly reduced in patients with tumors in outer quadrants , but increased in inner quadrants or central location . these authors stated that in patients with left - sided breast cancer , the risk of the relatively high dose to lad should be examined before treatment . in the present series with lad delineated according to guidelines by feng et al . , lad dose during pdr - bt of 10 gy boost dose applied in addition to wbrt , the dmean and dmax to the lad were on average 1 gy and 1.57 gy , respectively . however , in some cases , the latter dose constitutes up to 55% of the prescribed dose . as the lad is a serial organ , some authors postulated dmax to be applicable as a parameter in reporting lad exposure . in our series , mean d0.1cc was 1.42 gy , and ranged from 0.01 to 4.98 gy ( 0.1 - 49.8% of the tumor dose ) . we did show the difference between lad maximal , but not average doses among patients with tumors located in the upper and lower quadrants . in a series of 60 left - sided breast cancer patients who were treated with balloon - based hdr - bt apbi using mammosite ( hologic inc . , aliso viejo , ca , usa ) applicators , for balloons located in the upper inner quadrant of the breast , the average whole heart dmean was the highest . the lowest mhd ( 0.51 gy ) with 3d - conformal rt ( crt ) apbi as compared to multi - catheter and balloon hdr - bt apbi ( 1.58 gy and 2.17 gy , respectively ) for medially located left - breast tumors was demonstrated in an anthropomorphic phantom . in the most recent study by nilsson et al . based on coronary angiography , which was performed at a mean follow - up of 3.8 years ( range : 0.3 - 8.2 years ) after 3d - crt , the distribution of radiation dose in the segments of the lad differed markedly between left- and right - sided breast cancer . in the left - sided tumors in mid - lad component and in particular segment , 8 ( corresponding to distal lad ) doses approached the target of 50 - 60 gy . in 6 out of 7 left - breast cancer patients , it was substantially higher mean dose ranging from 30 to 55 gy to the distal lad than 3 to 13 gy to the heart . according to these authors , mid - lad is a critical vascular structure for developing late heart radiation effects . patients with right - sided cancer had low mhd in a range of 1 - 3 gy , and left - sided had higher mhd in a range of 3 - 13 gy . recent studies on left anterior descending ( lad ) coronary artery doses in breast cancer patients treated conservatively ( mean and maximum dose  the values are averaged over analyzed patients ) wbrt  whole breast radiotherapy , vdibh  voluntary deep - inspiratory breath - hold , fb  free - breathing , cwbrt  conformal wbrt , hdr - bt  high - dose - rate brachytherapy , apbi  partial breast irradiation , 3dcrt  three - dimensional conformal rt , imrt  intensity modulated radiotherapy , for - imrt  forward imrt , inv - imrt  inverse imrt , ht helical rt , vmat  volumetric - modulated arc rt , sib  simultaneous integrated boost , crt  conformal rt , t - imrt  tangential imrt , pdr - bt  pulsed - dose - rate brachytherapy  including 4 boosted cases , the most common wbrt dose fraction was 42.5 gy/16 fraction  depending on the lad s segment in wbrt for left - sided breast cancer , the lad dose distribution varied among studies and depended on the technique used , being the highest with free - breathing ( fb ) crt [ 13 , 16 , 18 , 21 ] . techniques to reduce cardiac irradiation dose include two - tangential or multi - beam intensity - modulated rt ( imrt ) , prone positioning , and breath holding techniques . however , each of them has some limitations , which should be considered in clinical practice . intensity - modulated rt in left breast cancer is associated with an improvement in dose homogeneity in the breast as well as reduction in cardiac dose , while the integral dose to the thorax , lungs , and contralateral breast is often increased . in terms of lad dose , dmean of the lad for prone position is substantially lower compared to supine position , but at the expense of a higher mhd . volumetric - modulated arc radiotherapy ( vmat ) resulted in a significant further reduction in both dmean and dmax of the lad compared with tangential imrt , based on deep inspiration breath - hold ( dibh ) . plans based on dibh resulted in a dose reduction compared with fb for all heart and lad parameters . notably , vmat - dibh is associated with 30% greater v5gy , as well as greater dose to the contralateral breast . study investigated supine voluntary deep - inspiratory breath - hold ( vdibh ) and fb techniques to deliver 40 gy in 15 fractions demonstrated significant reduction of ntdmean of the lad ( a biologically equivalent mean of total dose to tissue normalized to 2 gy fractions using a standard linear quadratic model , / = 3 gy ) for supine vdibh than fb prone technique ( 2.9 and 7.8 ; p < 0.001 ) . overall , cardiac doses were low for both techniques . deep - inspiratory breath - hold for left - sided breast cancer was associated with 43.5% reduction in dmean of the lad , as compared to fb wbrt by others . comparison among current different irradiation techniques ( wbrt , hdr - bt apbi , and 3d - crt apbi ) demonstrates that wbrt appears to be the most challenging , especially for patients with large breasts or when significant set - up errors are anticipated with greater probability of having cardiovascular events in the future . apart of apbi and modern external beam rt technique , intra - operative rt could further minimize dose to the coronary arteries . most patients in our series were hypofractionated with the uk standardization of breast radiotherapy trial ( start ) schedule of 40 gy in 15 fractions . applying the relative seriality model , the risk of cardiac death at 15 years of 1.4% for conventional schedule ( 50 gy in 25 fractions ) and 0.7% for start regimen was assumed . the others reported no statistically different cardiac mortality at 15-year follow - up among left - sided breast cancer patients treated with either conventional or hypofractionated wbrt . cardiac damage is correlated to the heart - absorbed dose , which is greater for left- than right - breast irradiation and evidently in boosted patients . the mean lad dose from left - sided wbrt was approximately five times higher than the dose from right - sided irradiation with the distal lad receiving the highest doses ( > 30 gy ; 75% of tumor dose ) , and the right and circumflex coronary arteries received approximately 2 gy mean dose . in this study , patient - to - patient variability in mean dose was the greatest for lad dose from left - sided irradiation , high lad dose was associated with high mhd , and the patient with the highest mhd ( 4.4 gy ) also had the highest lad dose ( 21.3 gy ) . they reported that lad dmean for left - tangential irradiation has decreased from 63.6% in the 1970s to 19.0% of tumor dose in 2006 . apart from historical changes in heart doses during breast cancer rt , the part of heart , particularly the anterior myocardial wall with lad lying on this surface , is receiving a dose of 20 gy , which determine the risk of ischemic heart disease for years after rt . for this analysis , the lad was retrospectively contoured by one author according to feng et al . guidelines . a multi - center study from denmark and the uk demonstrated substantial inter - observer variation in the estimated dose to the lad , even when guidelines for delineation were applied [ 12 , 28 ] . for the heart , there was little inter - observer variation in the estimated dose . organ motion during the treatment including inter - fraction variations is another factor influencing the lad estimated dose . in this series , the maximal dose for lad with 5 mm margin was on average 1.99 gy , and ranged from 1% to 75% of the tumor dose . given the geometric uncertainties , it was postulated to consider all cardiac dose parameters including v4gy and v25gy , along with mhd , when assessing the risk of future cardiac morbidity . for interstitial bt with the use of both metal and plastic catheters , the planning system applied was demonstrated to influence the dose to various volumes of interest [ 29 , 30 ] . in patients with breast cancer , it is intended to minimize , as much as possible , the heart volume that is irradiated without compromising the target coverage . recent implementation of 3d techniques has allowed delineation of the heart and coronary artery during rt planning processes including bt . the lad dose for patients with left - sided breast cancer should be routinely examined ( should be kept as low as possible ) and reported to clarify its clinical consequences , and eventually establish constraints for this artery . our data demonstrated that the mean lad dose in interstitial multi - catheter pdr - bt boost of 10 gy in - left breast is , on average , low . however , higher dose in individual cases may result in clinically relevant late cardiac toxicity ; therefore , in selected patients , the boost dose may require alternative approaches .