breast conserving therapy ( bct ) is currently considered as the standard management of early breast cancer .
reduced risk of local recurrence in patients administered a boost dose of 16 gy to the tumor bed in addition to 50 gy delivered to the whole breast , was confirmed in a large randomized trial [ 1 , 2 ] .
boost options include interstitial brachytherapy ( bt ) , electron or photon therapy , all following or preceding whole breast radiotherapy ( wbrt ) using external beam [ 1 , 3 , 4 , 5 , 6 , 7 ] . in all above approaches
, the extent of boost tumor volume may be incorrect if the tumor bed is determined using clinical parameters ( e.g. , palpation , pre - operative mammography , scar position , operative and pathology reports , or surgical clips placed at the excision site boundaries ) [ 8 , 9 , 10 ] .
the direct visualization of the operative site during surgery allows for decreasing the risk of  geographical miss  in determining the target volume .
pulsed - dose - rate ( pdr ) treatment is a bt modality combining the physical advantages of high - dose - rate ( hdr ) technology ( isodose optimization , radiation safety ) with radiobiological advantages of conventional low - dose - rate ( ldr ) bt . despite its favorable radiobiological features , pdr - bt has rarely been used as a component of bct . here ,
study group included 96 consecutive patients with microscopically confirmed early breast cancer , 17 of whom , with initial t1 - 3 or n1 - 2 tumor , received induction chemotherapy .
all patients underwent bct between may 2002 and october 2008 , including peri - operative pdr - bt boost following intra - operative bt tube placement to the primary tumor excision site ( table 1 ) and were technically suitable for bt .
breast carcinoma was primarily diagnosed using excisional or tru - cut biopsy in 59 women ( 61.5% ) and by fine needle aspiration biopsy in the remaining 37 patients ( 38.5% ) .
flexible tubes were implanted during breast conserving surgery ( bcs ) including primary tumor excision or re - excision , with immediate tumor cavity reconstruction using surrounding breast tissue in all but one case .
the bt implant covered the tumor excision site and the 1 - 2 cm margin of normal breast whenever possible . the number of tubes ranged between 4 and 17 ( median : 9 ) .
in most of patients , in order to guide needles , the standardized templates for a triangular array with a space of 10 - 14 mm were used . on the following day , 2d radiographic verifications of tube placement with the skin markers were taken , digitized , and entered into a bt planning system ( plato , version 13.7 or 14.1 , nucletron , an elekta company , elekta ab , stockholm , sweden ) .
the skin dose was reduced by keeping a distance of at least 10 mm from the first dwell position of the stepping source .
a total dose of 15 gy ( 1 gy per pulse repeated every hour ) was delivered .
brachytherapy was followed by external beam radiotherapy ( ebrt ) to the entire breast after the final histology of the excised tissue had been obtained .
patient and treatment characteristics ( n = 96 )  invasive and/or in situ ductal carcinoma present at an linked margin  including three patients with invasive ductal carcinoma ; an adequate margins in two of them was unachievable due to tumor adjunction to the chest wall , the third one underwent subsequent mastectomy v100  the percent volume of the post - implant receiving 100% of the prescribed dose , cc  cm follow - up data including cosmetic outcome assessed by a patient were obtained through personal contact or phone interview .
classification of side effects was performed using the common terminology criteria for adverse events version 4.0 , and late toxicity was reported if it occurred at least 6 months after bt .
statistical analysis was performed with spss software ( version 13.0 , ibm , usa ) .
time to event endpoints was estimated using kaplan - meier method from the date of brachytherapy to the date of any local , regional or distant relapse , or death from breast cancer , whichever occurred first , or to the date of last visit in case of no events .
on the average , tube implantation prolonged time of surgery by no more than 20 minutes . in three cases with deep located tumor ,
to construct the deep plane close to or upon the pectoralis minor muscle , tubes were implanted before excision cavity closing .
the average volume for the prescribed dose ( v100 ) was 34.1 cc ( range : 10.8 - 95.6 cc ) , and the median v100 for 93 patients with invasive tumor was 31.2 cc . at the time of the analysis , data regarding another dose - volume parameters were available in 36 patients ( 38.7% of all patients with invasive breast cancer ) . in this subgroup ,
the median volume of tissue receiving 150% ( v150 ) of the prescribed dose was 10.7 cc ( range : 2.87 - 33.44 cc ) , and the median dose homogeneity index [ dhi ] , defined as 1-(v150/v100 ) , was 0.72 ( range : 0.53 - 0.78 ) . in 91 patients , bt has started the day after the implant placement , and in five patients bt was delayed by 1 - 2 days .
these included eight cases with multiple adverse prognostic pathological factors diagnosed postoperatively , implying the superiority of mastectomy , one with the final diagnosis of lobular carcinoma in situ , and two with no malignant tumor ; all originally were diagnosed with fine needle aspiration as carcinoma .
the remaining 85 patients received wbrt , including one with massive axillary lymph node involvement , in whom breast irradiation was preceded by chemotherapy . except this case , the break between bt and wbrt ranged from 8 to 31 days ( median : 12 days ) .
no intense bleeding during surgery or at tube removal was observed and neither there were wound healing problems or significant skin reactions related to the implant .
one patient with re - excision experienced temporary peri - operative breast infection requiring antibiotic administration .
one patient with large - sized breast underwent subsequent surgical intervention due to grade 3 fat necrosis . in this case , wbrt was delayed up to 31 days after bt .
after median follow - up of 12 years ( range : 7 - 14 ) , one case of  true  local recurrence and one regional nodal recurrence were observed ( 1.2% each ) .
four patients ( 4.7% ) developed contralateral breast carcinoma ( of another histology in two patients or another histological grade in two patients ) .
six years after bct , one patient presented with angiosarcoma within the irradiated breast outside of the primary breast cancer .
another seven patients ( 8.2% ) developed second cancer including lung , ovarian , colon , skin cancer , and lymphoma .
apart from a case with angiosarcoma and a case with disseminated ovarian cancer , six relapsed breast cancer patients died due to cancer dissemination .
the actuarial 5- and 10-year disease - free survival was 90% ( 95% ci : 84 - 96% ) , and 87% ( 95% ci : 80 - 94% ) , respectively , for the whole cohort of 93 invasive breast cancer patients , and 91% ( 95% ci : 84 - 97% ) and 89% ( 95% ci : 82 - 96% ) , respectively , for patients who completed bct .
in 58 out of 64 ( 91% ) assessable patients , a good or excellent self - assessed cosmetic result was obtained .
one patient with fair cosmetic effect had no tumor excision site reconstruction during bcs , and another one , due to centrally located tumor , required the nipple - areolar complex excision .
intra - operative irradiation using electron beams , photon beams , or bt tube implantation provides a high precision boost , thus minimizing the risk of a  geographical miss 
we demonstrated the feasibility , good tolerance , and efficacy of the peri - operative bt using pdr .
interstitial pdr - bt boost seems to be particularly suitable component of bct , owing to its hypothetical favorable cosmetic outcomes .
high local control and satisfactory cosmesis with pdr boost following the whole breast ebrt in breast cancer was reported by other authors [ 4 , 5 ] .
the rationale for a bt boost is the delivery of a high dose to the tumor bed with reduced exposure of the skin , lung , and subcutaneous tissue .
the important advantages of intra - operative implant include reduced risk of  geographical miss  , shortening the treatment time , and avoidance of another anesthesia .
an apparent limitation of this approach is the lack of the full pathology assessment , especially regarding the margin status at the time of bt . in this series ,
28 patients ( 29% ) underwent a re - excision , and in the breast cancer group the tumor resection margins were tumor - free in 85% of patients . among cases with positive or close margin ,
positive pathologic margin has been considered a major risk factor for ipsilateral breast tumor recurrence ( ibtr ) , although the use of higher boost dose in these cases is debatable [ 16 , 17 ] .
a substantial risk of residual disease was reported for breast cancer patients with < 2 mm margin of excision . in the large retrospective study of 8485 early breast cancer patients with 5% ibtr incidence at 10-years ,
the invasive carcinoma margin status did not influence the risk of local relapse . in this cohort
, 9% of patients underwent a re - excision , and ibtr - free interval was longer for patients who received a rt boost or systemic therapy . a multidisciplinary consensus from 2014 defined an adequate breast cancer margin as no ink on tumor .
the role of surgical resection margins after breast - conserving surgery is summarized in recently published senonetwork recommendations .
this document proposes standards for investigating resection margins and recommends in patients with positive margins re - excision or mastectomy , or increasing the boost dose during radiotherapy . in case of negative margins ,
boost administration and its dose depend on the estimated risk of local recurrence , which is linked to demographic and pathological tumor features as well as the width of surgical margin . in this
series , diagnosis was established using excisional or tru - cut biopsy in the majority of patients ; nevertheless , in 11.4% of patients subsequent wbrt was omitted due to the postoperative pathology findings .
all these patients were primarily diagnosed by fine needle aspiration cytology used in the first period of this study .
thus , obtaining the definite diagnosis by a tru - cut biopsy seems to be essential in all patients considered for this strategy .
the optimal total and boost doses as well as bt dose rate , have not yet been determined in bct . in this series , 15 gy boost dose and 1 gy / pulse / h , followed by 50 gy or 40.05 gy and 42.5 gy ( 2 gy or 2.67 and 2.5 gy daily dose , respectively ) to the whole breast were used .
others administered 20 - 25 gy as the pdr boost following breast 50 gy ebrt [ 4 , 5 ] .
these authors found that the 25 gy boost dose is associated with a significantly higher rate of late toxicity compared to 20 gy .
others reported poorer cosmetic outcome in patients boosted with dose rates above 1 gy / h . until recently , in patients managed with bct , the standard wbrt dose was 50 gy .
the boost dose was used in 43 - 75% of patients enrolled in three out of four randomized trials of hypofractionated radiotherapy as a part of bct in early breast cancer patients .
immediate catheter placement reduces the target volume ; however , its determination remains subjective . in our series ,
this may allow for better cosmetic outcome but at the expense of potentially increased risk of local recurrence .
, in a series of patients with high risk of recurrence , reported the mean pdr boost volume of 57 cc . in the study by resch et al . , in which 60% of patients underwent quadrantectomy , 18% wide excision and 22% tumorectomy , the average volume for the  prescribed dose  was 83 cc . of note , in that study , the type of surgery did not impact the local control .
notably , excellent local control ( 1.6%  true local recurrence  at 10 years for patients after quadrantectomy , 0% for wide excision , and 2.2% for tumorectomy ) was accompanied by a fair cosmetic effect ( excellent or good cosmetic effect in only 38% of patients ) . in this series ,
the dhi was available for two patients , and in both cases , it was 0.68 ( v150 of 10.7 cc and 17.8 cc ) .
the reported incidence of fat necrosis including symptomatic / clinically overt cases varies considerably in particular studies , and is influenced by differences in patient characteristics , treatment , duration of follow - up , and diagnostic criteria for a diagnosis of fat necrosis .
no late fat necrosis was reported in the two above mentioned studies applying pdr bt boost at a dose of 15 - 25 gy following whole breast irradiation [ 4 , 5 ] . the median follow - up in these series was 30 months and 60.9 months .
in another small series with patients boosted with pdr bt with the median dose of 12.3 gy ( range : 12.0 - 20.3 gy ) ( median v100 of 55.2 cc , median dhi : 0.82 ) , in addition to 50.4 gy wbrt , the incidence of mammographically evident signs of fat necrosis was 9.0% at the median follow - up of 37.5 months , but no patient needed surgical intervention . after a median follow - up of 46 months , fat necrosis in one case ( 1.3% ) was observed in a series with hdr - bt ( median v100 of 94.49 cc ) performed immediately after completing wbrt .
the late toxicity data in patients treated with multicatheter interstitial hdr - bt as a form of accelerated partial breast irradiation ( apbi ) , suggest that v150 and v200 , as well as anthracycline - based chemotherapy administered after apbi may be associated with an increased risk of fat necrosis . in another apbi study ,
acute breast infection and anthracycline - based chemotherapy , number of catheters , v100 , v150 , v200 , and integrated reference air - kerma were associated with fat necrosis . of these , v150 was independent treatment - related parameter .
in these studies , the mean v100 was 176 cc and 239 cc , respectively .
our series includes 17 breast cancer patients ( 17.7% ) who were administered preoperative chemotherapy , an increasingly used strategy . in this group ,
secondary angiosarcoma may develop in a lymphedematous arm , in the irradiated chest wall after radical mastectomy , and following bct .
this event is rare but associated with poor prognosis . in a large retrospective series of 18,115 breast cancers treated with bct , including 50 gy whole breast irradiation and a boost dose of 15 - 25 gy , post - irradiation angiosarcoma was diagnosed in only nine cases , after the median latency period of approximately 74 months .
adjuvant radiotherapy , an indispensable part of bct , is associated with the risk of second malignancy including all sarcomas and angiosarcoma . beside
radiotherapy , partial mastectomies and lymph node dissections were found to be independent risk factors for the development of angiosarcoma in breast cancer patients .
post - irradiation breast angiosarcoma , the most frequent second type of sarcoma after primary breast cancer , has been paradoxically increasingly reported since currently most women with breast cancer have long - term survival .
in addition , the increasing use of intensity modulated radiation therapy ( imrt ) and volumetric modulated arc therapy ( vmat ) , might be associated with a higher risk of mutagenesis . due to the higher number of fields and monitor units ,
these newer techniques have been shown to have greater out - of - beam doses including higher low dose exposure of the normal structures . whether angiosarcoma is induced by radiation or persistent edema , or
our patient with ypt2n1 breast cancer underwent axillary dissection and received irradiation at a standard dose of 50 gy in 25 fractions with tangential fields to the breast and the supraclavicular region .
thus , despite the lack of clinical lymphedema , she might have had some minimal subclinical lymph stasis involving the breast .
the addition of neoadjuvant chemotherapy consisting of 6 cycles of doxorubicin and docetaxel , might have also contributed to secondary malignancy in this patient .
peri - operative pdr - bt with tube implantation at the time of surgery seems to be a safe and convenient boost method allowing for good local control and satisfactory cosmetic effect .
the direct visualization of the operative site during surgery allows for precise defining of the tumor bed and decreases the risk of  geographical miss  in determining the target volume .
however , in a proportion of patients , the treatment plan should be verified after the final histology is obtained .
 purposeto evaluate peri - operative multicatheter interstitial pulsed - dose - rate brachytherapy ( pdr - bt ) with an intra - operative catheter placement to boost the tumor excision site in breast cancer patients treated conservatively.material and methodsbetween may 2002 and october 2008 , 96 consecutive t1 - 3n0 - 2m0 breast cancer patients underwent breast - conserving therapy ( bct ) including peri - operative pdr - bt boost , followed by whole breast external beam radiotherapy ( wbrt ) . 
 the bt dose of 15 gy ( 1 gy / pulse / h ) was given on the following day after surgery.resultsno increased bleeding or delayed wound healing related to the implants were observed . 
 the only side effects included one case of temporary peri - operative breast infection and 3 cases of fat necrosis , both early and late . in 11 patients ( 11.4% ) , subsequent wbrt was omitted owing to the final pathology findings . 
 these included eight patients who underwent mastectomy due to multiple adverse prognostic pathological features , one case of lobular carcinoma in situ , and two cases with no malignant tumor . 
 with a median follow - up of 12 years ( range : 7 - 14 years ) , among 85 patients who completed bct , there was one ipsilateral breast tumor and one locoregional nodal recurrence . 
 six patients developed distant metastases and one was diagnosed with angiosarcoma within irradiated breast . 
 the actuarial 5- and 10-year disease free survival was 90% ( 95% ci : 84 - 96% ) and 87% ( 95% ci : 80 - 94% ) , respectively , for the patients with invasive breast cancer , and 91% ( 95% ci : 84 - 97% ) and 89% ( 95% ci : 82 - 96% ) , respectively , for patients who completed bct . 
 good cosmetic outcome by self - assessment was achieved in 58 out of 64 ( 91% ) evaluable patients.conclusionsperi-operative pdr - bt boost with intra - operative tube placement followed by ebrt is feasible and devoid of considerable toxicity , and provides excellent long - term local control . however , this strategy necessitates careful patient selection and histological confirmation of primary diagnosis . 