uterine serous carcinoma ( usc ) is an uncommon but aggressive form of endometrial adenocarcinoma .
its pattern of spread favors the peritoneum and upper abdomen , and thus adjuvant management is typically more aggressive than for the endometrioid subtypes , even when it presents in early stages . in the united states ,
surgical staging of usc includes total hysterectomy , bilateral salpingo - oophorectomy , peritoneal washings , omentectomy , and pelvic and para - aortic lymph node dissections .
historically , whole abdominal radiotherapy was the mainstay of adjuvant therapy , even in optimally resected stage i disease [ 3 , 4 ] .
recently , studies have demonstrated a benefit with the use of adjuvant chemotherapy [ 57 ] .
contemporary adjuvant treatment of early stage ( stage i - ii ) disease following comprehensive staging involves a combination of chemotherapy and smaller - field radiation therapy ( rt ) [ 5 , 6 ] , and an increasingly popular adjuvant treatment paradigm combines chemotherapy with intra - vaginal brachytherapy ( ivb ) [ 5 , 813 ] .
there have been few studies to date , which have addressed adjuvant ivb technique in early stage usc , and thus questions concerning ivb dose and sequencing with chemotherapy persist .
this topic was not covered in the guidelines for adjuvant vaginal cuff brachytherapy released by the american brachytherapy society in 2012 .
several recent institutional reports describe excellent 5-year vaginal recurrence rates of 0 - 3% using chemotherapy in combination with a common high - dose - rate ( hdr ) ivb regimen , 7 gy x 3 fractions prescribed to a depth of 5 mm from applicator surface [ 912 ] .
a recent phase ii evaluation of endometrial patients with high - intermediate risk factors , of which 35% of the population was usc , employed this same hdr regimen followed by three cycles of adjuvant chemotherapy .
there is modest support for an alternate ivb dose schedule for usc patients receiving chemotherapy based on a single retrospective report , in which hdr ivb was delivered twice per week in 6 fractions of 4 gy prescribed to the mucosal surface .
this fractionation schedule delivered an equivalent dose in 2 gy / fraction ( eqd2 )   of approximately 28 gy to the vaginal surface , which is approximately half of the mucosal dose used in the other series . at our institution , usc patients with localized disease who have undergone comprehensive surgical staging
are recommended chemotherapy with ivb . when our hdr program was first introduced in the 1990s , in the era of adriamycin - based chemotherapy ,
several cases of vaginal mucositis were noted by the treating physicians , and thus the hdr prescription for all usc patients receiving chemotherapy was modified from 7 gy x 3 to 7 gy x 2 prescribed to 0.5 cm from the cylinder surface .
this lower dose prescription translates into a total equivalent dose ( eqd2 ) of approximately 36 gy to the vaginal mucosal surface .
previously published results from our institution have demonstrated that this regimen appeared safe and effective , and resulted in significantly improved vaginal control when compared to outcomes of patients with localized usc who received chemotherapy alone .
chemotherapy for usc has since evolved , and for the past 15 years , six cycles of adjuvant carboplatin - paclitaxel ( c / t ) chemotherapy has become standard .
the ivb prescription dose at our institution for patients treated with this chemotherapy regimen has remained 2 fractions of 7 gy prescribed at 0.5 cm depth . in this report , we present the 5-year clinical outcomes of patients with early stage ( figo 2009 stage i - ii ) usc treated at our institution from 2000 - 2010 with contemporary c / t chemotherapy and this unique brachytherapy regimen .
institutional review board approval was granted to perform a retrospective chart review of all patients with stage i - ii usc treated at our institution in the years 2000 - 2010 .
patients with advanced - stage disease , or those with early stage disease who had received single modality therapy , external beam rt , other brachytherapy fractionation , or chemotherapy regimen other than c / t were excluded .
additionally , patients with biopsy - proven cancer but without residual cancer in their hysterectomy specimens were excluded .
analysis was limited to patients who received all aspects of their multi - modal treatment at our academic medical center .
all patients had biopsy - proven endometrial cancer and underwent total hysterectomy with surgical staging .
chemotherapy consisted of carboplatin ( auc = 5 - 6 ) and paclitaxel ( 175 mg / m ) in all patients , given every 3 weeks for 6 cycles .
intra - vaginal brachytherapy was delivered via a high - dose - rate ir-192 source .
patients were fit with a vaginal cylinder ( size ranging from 2.6 - 3.0 cm ) at the time of radiation consultation .
a dose of 14 gy in 2 fractions ( 7 gy each ) was prescribed to a depth of 0.5 cm from the vaginal cylinder surface .
active source length was standardized for all patients to six dwell positions , separated by 1 cm spacing , for an active length of 5 cm .
all plans were created on a phantom with a 10 ci nominal source , and dwell times were optimized to ensure a dose of roughly 10.5 - 11 gy at the cylinder surface .
ct - simulation was not performed , and normal tissue point doses were not recorded .
intra - vaginal brachytherapy was started early in the course of adjuvant treatment , typically with the first fraction delivered one week prior to and the second fraction one week following the second cycle of chemotherapy . administering chemotherapy the same week as brachytherapy was avoided to decrease likelihood of overlapping toxicities .
patients were followed by routine clinical examination , pap smears , and tumor markers every three months .
based on review of physician - recorded toxicities listed in routine follow - up documentation , toxicity scores were assigned retrospectively with the common terminology criteria for adverse events ( ctcae ) v4.0 .
kaplan - meier methods were used to estimate 5-year recurrence - free survival ( rfs ) and overall survival ( os ) .
time to recurrence , last follow - up , and/or death was calculated from the date of hysterectomy .
log - rank test was employed to identify patient , tumor , and treatment characteristics associated with rfs and os .
given the small sample size and paucity of events , a multivariate analysis was not performed .
fifty - six patients were identified with figo 2009 stage i - ii usc treated from 2000 - 2010 with adjuvant c / t chemotherapy along with 2 fractions of ivb ( 7 gy each ) .
the majority had undergone comprehensive surgical staging including pelvic dissection ( 96% , median nodes removed = 18 , range : 6 - 47 ) , para - aortic dissection ( 80% , median nodes removed = 3 , range : 1 - 37 ) , omentectomy , and peritoneal cytology ( 93% ) .
the median age was 66 ( range : 47 - 81 ) . according to figo 2009 staging ,
42 patients ( 73% ) were stage ia , 18% were stage ib , and 9% were stage ii . of the ia patients , 14 ( 33% ) had disease confined to the endometrium , and 28 ( 67% ) had ia invasive disease . among the entire cohort , 21% had myometrial invasion  50% , and 29% had lymph - vascular space involvement . forty percent of tumors consisted of usc mixed ( more than 10% usc ) with other endometrioid or high grade histologies .
patient and tumor characteristics ( n = 56 ) all 56 patients completed 2 ivb fractions , and 53 patients ( 95% ) completed all 6 cycles of chemotherapy .
the median time from surgery to first ivb fraction was 49 days ( range : 30 - 113 ) .
the median follow - up time , calculated from the date of hysterectomy , was 49 months ( range : 9 - 145 ) .
late toxicities ( recorded > 90 days post - treatment ) were as follows : forty - seven patients ( 84% ) had no toxicities recorded .
one patient who was disease - free with a history of ulcerative colitis had grade 2 diarrhea and tenesmus .
two patients ( 3.6% ) had grade 2 vaginal toxicities ; one developed grade 2 vaginal stricture with banding , one was noted to have grade 2 vaginal atrophy .
smoking history was associated with poorer os ( p = 0.008 ) and lvi ( lymph - vascular space invasion ) was associated with poorer rfs ( p = 0.003 ) .
age > 70 had a borderline significant effect on os ( p = 0.062 ) and smoking had a borderline effect on rfs ( p = 0.076 ) .
depth of myometrial invasion  50% was significantly associated with both poorer rfs ( p < 0.0001 ) and os ( p = 0.001 ) . among patients with  50% myometrial invasion ,
the 5-year rfs and os was 47% and 72% , versus 94% and 97% for those with < 50% myometrial invasion . 
 
stage i - ii uterine serous carcinoma ( n = 56 ) recurrence - free survival 
stage i - ii uterine serous carcinoma ( n = 56 ) patient / tumor characteristics and univariate log - rank results for overall ( os ) and relapse - free survival ( rfs ) the percentage of patients with recurrence was 14.3% ( n = 8 patients ) . in all cases ,
the median time to recurrence was 28.5 months ( range : 16 - 69 ) .
neither of the two patients with positive peritoneal cytology at diagnosis ( old figo 1988 stage iiia ) developed recurrence .
one patient with no myometrial invasion ( old figo 1988 stage ia ) developed recurrence .
the para - aortic region was involved in 2 patients and was an isolated failure site in 1 patient .
there were no isolated vaginal recurrences , however , there was one vaginal apex recurrence at 19 months in a patient with simultaneous lung metastases .
data concerning optimal ivb dose - fractionation in combination with chemotherapy for usc are lacking .
the present report of 56 patients with surgically staged localized usc found that following aggressive surgery , an ivb dose of 14 gy in two fractions prescribed to 5 mm depth ( surface eqd2 36 gy ) in combination with 6 cycles of c / t chemotherapy resulted in excellent disease control , acceptable toxicity , and very low rates of vaginal / pelvic failure . the 5-year rfs and os were 85% and 93% , respectively .
these results do not appear inferior to those of standard - dose brachytherapy ( 18 - 21 gy in 3 fractions prescribed at 0.5 cm , surface eqd2 54 gy ) [ 912 , 15 , 17 ] , and appear comparable to that achieved with other low - dose schema ( 24 gy in 6 fractions , prescribed to vaginal surface , surface eqd2 28 gy ) . for endometrial cancer patients with endometrioid histology , there is evidence and growing interest in the concept that a lower vaginal surface dose may be as effective as the higher  classic  brachytherapy prescription dose .
for example , one randomized trial from sweden of 290 low - risk endometrial patients showed that excellent rates of vaginal control were achievable with six fractions of 2.5 gy prescribed to 5 mm from the applicator surface ( surface eqd2 30 gy ) .
a randomized study sponsored by the portec group ( portec-4 ) is investigating whether three fractions of 5 gy prescribed at 5 mm ( surface eqd2 33 gy ) is non - inferior to three fractions of 7 gy ( surface eqd2 54 gy ) .
we believe that further study of alternate dose schema in usc patients receiving chemotherapy is worthwhile .
the incidence of grade 1 - 2 vaginal toxicity , including atrophy , shortening , and stenosis is approximately 35% when prescribing standard dose brachytherapy
. concomitant chemotherapy may increase the incidence of vaginal dryness and discomfort in patients undergoing ivb , and furthermore , sexual dysfunction can be related to changes in body image associated with chemotherapy - induced menopause and hair loss .
therefore , lowering the dose to the vaginal mucosa in patients receiving chemotherapy may improve toxicity , however , to our knowledge , this concept has not yet been studied . in the present series
, there were no grade 3 - 4 vaginal toxicities , and grade 2 vaginal toxicities among the 56 patients were recorded in only two patients ( 3.6% ) , which is remarkably low , and compares favorably to the literature .
however , it must be noted that due to the retrospective nature of this report , toxicity recording was not standardized , and thus grade 1 - 2 toxicities were likely under - reported . to truly assess a benefit of this lower dose regimen compared to standard - dose brachytherapy , particularly concerning vaginal toxicities , prospective , standardized recording of toxicities
the pattern of recurrence of usc differs from that of its endometrioid counterpart , and abdominal / peritoneal recurrence is described in even clinical stage i disease [ 1 , 2 ] .
support for platinum / taxane chemotherapy regimens with or without rt is mounting [ 57 ] .
critics of the use of rt in early stage usc might wonder , if two ivb fractions are as good as three , why not abandon rt completely .
however , eliminating rt in early stage usc appears to result in very high rates of vaginal recurrence [ 5 , 22 , 23 ] . in one study of 74 stage
i usc patients who were surgically staged , none of 43 patients who received radiation to the vaginal cuff recurred locally , however , six of the 31 ( 19% ) patients who were not treated with vaginal radiation recurred at the vaginal cuff . in another report of 60 usc ( and other unfavorable histology ) patients who had adjuvant radiation therapy ,
one had a recurrence at the vaginal apex , whereas of the 65 patients who did not have adjuvant radiation , 8 had a local - regional recurrence , which included 3 with a vaginal only recurrence , 1 vaginal , and pelvic recurrence and 4 had pelvic recurrence .
further , in an investigation of the pattern of failure among 23 early stage usc patients , of those treated without rt , five of nine failures were within the pelvis , of which 4 relapsed in the vagina ; however , there were no pelvic failures in women treated with adjuvant rt .
thus , although the optimal ivb dose fractionation scheme for treatment of patients with early stage usc is not known , the current available data do support the importance of multi - modality therapy including comprehensive surgery , chemotherapy [ 6 , 7 ] , and rt [ 5 , 22 , 23 ] .
there is a lack of clear evidence concerning the preferred radiotherapy approach for usc ; thus adjuvant radiotherapy practices for early stage usc continue to vary by country and by institution .
some believe that ivb alone may be inadequate due to risk of non - vaginal pelvic recurrences , and therefore tumor - directed pelvic rt in combination with chemotherapy is practiced by many .
for example , at md andersen cancer center , pelvic radiotherapy in combination with paclitaxel resulted in 5-year pfs of 83% among stage i - iiia usc patients . yet
other institutions have supported ivb in favor of pelvic rt due to its favorable side effect profile and the predilection of usc for distant relapse .
for example , at memorial sloan - kettering cancer center , a retrospective analysis of 77 early stage usc patients treated with ivb without pelvic rt ( majority also receiving chemotherapy ) found 5-year pelvic recurrence of 6% .
these authors concluded that this rate was not high enough to justify routine use of pelvic rt in this population . more insight into optimal radiotherapy and chemotherapy combinations for
this rare disease , both with respect to disease control as well as toxicity , will likely emerge once data mature from the recently accrued gog 249 ( pelvic rt versus ivb + chemo ) and ongoing portec-3 ( pelvic rt versus pelvic rt + chemo ) trials , both of which include usc patients within the study populations . while the results of our early stage usc cohort were excellent overall , the majority of patients ( 73% ) had stage ia disease . on closer analysis ,
stage ib patients appear to fare less well , with a 5-year rfs of 47% for those with deep myometrial invasion .
the association of stage ib with relatively high risk of extra - pelvic failures is in agreement with multiple other studies [ 8 , 24 , 26 , 27 ] .
a recent population - based study from british columbia , which studied pelvic rt in combination with 3 cycles of c / t chemotherapy   found a 5-year disease - free survival of 48.5% for patients with stage ib disease , and a majority of the recurrences were extra - pelvic .
the application of more targeted therapies to treat usc , even in uterine - confined disease with deep myometrial invasion , may be needed . in our series
this patient had numerous risk factors for recurrence including > 50% depth myometrial invasion and lymph - vascular space involvement , as well as simultaneous lung metastases , as shown in table 3 .
whether the vaginal relapse may have been prevented had a higher dose of brachytherapy and/or pelvic radiotherapy been utilized is not known .
overall , the 2-year vaginal failure rate of 2% in this series appears comparable to that of similar cohorts of early stage usc and/or high - risk endometrial patients , which have used a median dose of 21-gy in 3 fractions , and reported 2 - 5 year vaginal failure rates of 2 - 4% [ 1012 , 15 , 26 ] .
direct comparison , however , is not possible given the heterogeneity of stages ( percentage stage ia versus ib ) and histologies ( pure usc versus mixed ) .
in addition , the cohort of patients studied is small , although comparable to other publications reporting on this rare disease .
it is important to note that all patients in this series were treated with comprehensive aggressive staging by experienced gynecologic oncologists , and therefore this regimen may not be satisfactory for women who have had less aggressive surgery .
furthermore , the population described had all received c / t chemotherapy , and hence the use of 2 fractions of 7 gy as described in this report may not be appropriate for women with other chemotherapy regimens , fewer than 6 cycles of chemotherapy , or non - serous histology . moreover , given that , a majority of patients in this series ( 79% ) had < 50% myometrial invasion , our findings may not be generalizable to patients with stage ib or higher disease .
also , caution should be used in applying this regimen when using cylinder sizes smaller than 2.6 cm , due to the relatively high fractional surface dose to the mucosa with this regimen .
lastly , given the retrospective nature of the study , information on vaginal toxicity was not recorded consistently .
an ongoing prospective investigation at our institution examines whether this reduced - dose ivb regimen is associated with improved toxicity compared to more standard ivb schema .
debate continues concerning the preferred radiotherapy approach for early stage usc . in our series , when combined with contemporary chemotherapy , adjuvant hdr ivb delivered as 2 fractions of 7 gy prescribed at a depth of 0.5 cm resulted in excellent vaginal / pelvic control rates for localized usc .
further study of brachytherapy technique in usc investigating the optimal dose , number of fractions , time interval between fractions , and when to schedule with chemotherapy is warranted .
 purposeto evaluate our institutional experience combining carboplatin - paclitaxel ( c / t ) chemotherapy with high - dose - rate ( hdr ) intra - vaginal brachytherapy ( ivb ) following comprehensive surgical staging in localized uterine serous carcinoma ( usc).material and methodsinstitutional chart review identified 56 patients with figo 2009 stage i - ii usc treated between 2000 - 2010 . 
 patients underwent total hysterectomy , bilateral salpingo - oopherectomy , and comprehensive surgical staging including pelvic and para - aortic lymph node dissection , omentectomy , and peritoneal cytology . 
 chemotherapy was 6 cycles of c / t , and the ivb dose was 14 gy in 2 fractions , prescribed to 0.5 cm from the cylinder surface . 
 kaplan - meier methods were used to estimate recurrence - free survival ( rfs ) and overall survival ( os).resultsthe median follow - up time was 49 months ( range : 9 - 145 ) . 
 the 5-yr rfs and os were 85% and 93% , respectively . in all cases of recurrence ( 
 n = 8) , the first site of failure was extra - pelvic . 
 there were no isolated vaginal recurrences , however , there was one vaginal apex recurrence recorded at 19 months in a patient with simultaneous lung metastases . 
 thus , the 2-year vaginal rfs was 98%.conclusionsexcellent vaginal / pelvic control rates were observed . further study of hdr brachytherapy dose and fractionation in combination with chemotherapy is worthwhile . 
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Material and methods
Results
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