endometrial carcinoma is the most common gynecologic malignancy , with an estimated 40 100 incident cases and 7470 deaths in 2009 .
the current standard of care for patients with endometrial cancer consists of surgical staging , including total hysterectomy , bilateral salpingo - oophorectomy , and pelvic and para - aortic lymph node dissection .
depending on the surgical stage and histological grade , the adjuvant treatment may include radiation therapy and/or chemotherapy . in approximately 10% of patients ,
however , there is a relative lack of consensus regarding the most appropriate management strategy for these patients .
patients with clinically occult stage ii disease usually have undergone simple hysterectomy rather than radical hysterectomy , which is then followed by adjuvant radiation therapy .
patients with clinical stage ii disease may be treated with preoperative ( neoadjuvant ) radiation therapy followed by simple hysterectomy , or alternatively , primary radical hysterectomy and possible adjuvant tumor - directed radiation therapy .
it is especially advocated for patients having co - morbidities that limit their candidacy for radical surgery , including obesity . in all patients with clinical stage ii disease , neoadjuvant
radiotherapy can decrease the size and extent of bulky cervical disease , making it easier to obtain clear surgical margins .
further , it avoids the increased morbidity associated with lymphadenectomy followed by radiation therapy , as is seen in cervical cancer .
conversely , advocates of primary treatment by radical hysterectomy cite the ability to debulk large tumor prior to attempting radiation therapy , to clarify the origin of the primary tumor as cervical or endometrial , and to clarify the stage and grade of disease prior to initiating adjuvant therapy .
most of the published literature on preoperative treatment is with low dose rate ( ldr ) brachytherapy [ 912 ] . due to the relative rarity of this clinical scenario ,
there is no published data on dose , fractionation or pathological response to high dose rate ( hdr ) intracavitary brachytherapy in the neoadjuvant setting .
the goal of this study was to evaluate pathological response , tolerance , and outcome with this latter approach .
twelve women clinically diagnosed with clinical stage ii endometrial carcinoma from 1999 - 2010 were treated with preoperative radiation therapy .
all patients had biopsy - confirmed endometrial cancer and had pretreatment ct scan and/or mri for staging .
the dose of external beam ( ebrt ) was 45 - 50.4 gy in 25 to 28 fractions followed by hdr brachytherapy .
the hdr brachytherapy was done with placement of a smit sleeve and tandem and ring applicator . prior to 2004
, three patients received a dose of 4 gy in four fractions , but since that time all patients received doses between 5 - 5.5 gy in three fractions .
initially , for the first six patients , the dose was prescribed to point a with orthogonal film based dosimetry .
the last six patients were treated with mri or ct based planning with the clinical target volume being the entire uterus and cervix ( fig .
1 ) . demographics , tumor histology , and pathological response to neoadjuvant hdr brachytherapy prior to simple hysterectomy in twelve patients with clinical stage ii endometrial carcinoma histological and figo grading from endometrial biopsy , not surgical specimen eqd2  equivalent dose in 2-gray increments , pr  partial response , cr  complete response  microscopic residual disease , ned  no evidence of disease , awd  alive with disease sagittal ( left ) and coronal ( right ) view showing clinical target volume ( red ) covered by prescription isodose line of 100% ( red ) simple hysterectomy with lymph node sampling was performed four to eight weeks after the last brachytherapy treatment .
the total doses from ebrt and brachytherapy were summated and normalized to a biologically equivalent dose of two gy per fraction ( eqd2 ) using the linear quadratic model and  10 gy .
all patients were followed every three months for the first two years , and every six months thereafter , with vaginal cytology at each surveillance visit .
the median age was 57 ( range 41 - 76 ) with median body mass index ( bmi ) of 35 ( range 29 - 45 ) .
all patients completed the planned course of preoperative radiation therapy with a median eqd2 dose of 65.0 gy ( range 56.3 - 75.4 gy ) .
all patients had simple hysterectomy with lymph node sampling with uneventful recovery from the operation .
complete pathological response ( pcr ) was seen in two patients ( 17% ) while five patients ( 42% ) had only microscopic residual disease confined to either the endometrium or cervical glands .
two patients were found to have para - aortic disease and received adjuvant para - aortic radiation .
two patients with high grade pathology ( one each with serous and clear cell histology ) also received adjuvant chemotherapy after surgery . at a median follow up of 37 months ( 1 - 91 months )
, one patient has developed recurrence at the vaginal apex six months after completing initial therapy and is alive with the disease at 91 months , while another developed a lung recurrence at 28 months .
one patient has died of comorbidities at 86 months with no evidence of the disease at last follow up .
two - year actuarial disease - free and cause - specific survivals were 88% and 100% , respectively ; these were calculated for only those patients with at least two years of follow - up .
the goals of this neoadjuvant therapy are to shrink the primary disease , to treat pelvic nodes and parametria , and to make the patient more suitable for simple hysterectomy .
there is no published experience with hdr intracavitary brachytherapy as preoperative treatment for endometrial cancer .
the american brachytherapy society in its published guidelines for hdr brachytherapy for endometrial cancer have not recommended a dose or fractionation schedule for preoperative hdr brachytherapy for stage ii endometrial cancer , likely due to the lack of published data .
multiple studies have shown equivalency of hdr and ldr brachytherapy for cervical cancer [ 14 , 15 ] .
the advantages of hdr include short treatment time , ability for optimization , and a lack of radiation exposure to healthcare personnel .
since 2004 , our institution has followed a fractionation schedule of three fractions of 5 - 5.5 gy to deliver a dose equivalent to 65 - 70 gy .
the schedule has been well tolerated , has shown a good response rate , and has not revealed significant morbidity .
more recently , we have integrated three - dimensional planning for hdr brachytherapy , which helps to conform better the dose to the tumor while reducing the dose to critical organs ( fig .
1 ) . the results of this small series are comparable to published studies using ldr brachytherapy . in a series of 74 patients with stage ii endometrial cancer treated at the university of kentucky ( uk ) with a combined dose of 65 gy
, the complete pathological response rate was seen in 31% and the residual disease confined to endometrium in 29% [ 10 , 11 ] . in our study , which had a median eqd2 dose of 66.31 gy , pcr was seen in 22% , with superficial residual disease confined to the endometrium in 33% . in the uk series ,
para - aortic nodal disease was noted at the time of surgery in five patients , compared to two patients in our series .
patients with cervical involvement are at increased risk of both pelvic and para - aortic nodal involvement ; since only the pelvic nodes are treated during the whole pelvic radiation therapy given preoperatively , para - aortic nodal sampling at the time of surgery should be considered . the optimal management for clinical stage ii disease that provides a better outcome , in terms of disease control and morbidity ,
it is difficult to study prospectively because of the comparative rarity of this clinical scenario . in a retrospective analysis of 184 consecutive patients with clinical or pathologic stage ii endometrial cancer treated with definitive intent with either preoperative or postoperative radiation therapy ,
only the grade and histology were found to be independent predictors of disease free survival .
since a subset of these patients are not ideal candidates for radical surgery because of medical co - morbidities , advanced age , and obesity , the preoperative radiation therapy followed by simple hysterectomy may be a better option .
ours is the first published series using hdr and shows the hdr fractionation schedule , as done in our series , is well tolerated and would be an option for patients treated with neoadjuvant radiation therapy .
 purposewe sought to evaluate pathological response , tolerance , and outcome after preoperative ( neoadjuvant ) high dose rate brachytherapy in a small series of patients with clinical stage ii endometrial carcinoma , and to evaluate a dose and fractionation protocol for this treatment.material and methodstwelve women diagnosed with clinical stage ii endometrial carcinoma from 1999 - 2010 were treated with preoperative radiation therapy . 
 their medical charts were retrospectively analyzed for hdr treatment regimen , pathological response , and longitudinal outcomes . 
 radiation doses were normalized to a biologically equivalent dose of 2 gy per fraction ( eqd2).resultstwo patients had complete pathological response to neoadjuvant therapy ; five more had only microscopic residual disease at the time of surgery . at a median follow up of 37 months ( 1 - 91 months ) 
 , one patient has developed recurrence at the vaginal apex six months after completing initial therapy , while another developed a lung recurrence at 28 months . 
 two - year disease - free and cause - specific survivals were 88% and 100% , respectively.conclusionsour small study shows that the hdr fractionation schedule , as done in our series for preoperative radiation therapy for clinical stage ii endometrial cancer , is well tolerated and would be an option for patients treated with neoadjuvant radiation therapy . 