peri - urethral tumors in females are masses that grow around the urethra and do not communicate with the urethra , bladder , or vagina ( figure 1 ) . these include lesions located in para - urethral and sub - urethral space [ 2 , 3 ] . they can be both benign as well as malignant [ 1 , 4 ] . the benign lesions include leomyomas , hamartoma , urethral caruncles , skene 's gland abscess / cysts , urethral diverticulum , gartner 's duct cyst , etc . . malignant lesions are rare and can be primary or recurrent / secondary from other primary malignancies like cervical , endometrial , or rectal carcinoma . primary malignancies include adenocarcinoma , squamous cell carcinoma , histiocytoma , melanoma , and sarcoma . the distinction between urethral , peri - urethral , and anterior vaginal wall lesions may be difficult because of their anatomic proximity and overlapping clinical features . imaging techniques such as computed tomography / magnetic resonance ( ct / mr ) ( preferably mr ) are helpful in diagnosis [ 7 , 8 ] . cysto - urethrogram helps in excluding the urethral origin and invasion . clinical photograph showing a tumor in the periurethral region protruding in the vagina the literature on female peri - urethral cancer ( puc ) is extremely limited , and it is very challenging to predict the clinical course and decide management . treatment options include surgery and radiation therapy ( rt ) , and the decision is usually individualized . surgery is often tried in the form of 1 ) local excision for small tumors and requires plastic repair ( urethroplasty ) , and 2 ) pelvic exenteration for larger lesions , which is associated with significant morbidity . radiation therapy can be employed in the form of brachytherapy alone for early lesions and external beam radiation therapy ( ebrt ) with or without brachytherapy for advanced lesions . treatment with ebrt is quite challenging due to anatomic location and poor tolerance of the adjoining organs like vulva , urethra , and rectum . interstitial brachytherapy ( ibt ) can precisely deliver the radiation to the tumor with sparing of the adjacent organs . role of ibt has been reported in a small series , though in patient populations having recurrent puc . we report our first ever experience in the literature to evaluate the role of hdr - ibt in female puc , primary as well as recurrent . between 2008 and 2013 , 10 female patients with puc were treated with hdr - ibt with or without ebrt at our center . the decision of treatment was taken in combined gynecologic oncology clinic by a team comprising of gynecologists and radiation oncologists . pretreatment evaluation consisted of detailed clinical examination , routine blood investigations , plain x - ray chest , ct / mr imaging of the abdominopelvic region , and histopathological examination of the primary lesion . alone hdr - ibt was usually the preferred treatment for patients having small lesions ( < 3.0 cm ) . for lesions larger than 3.0 cm , ebrt was added to ibt for regional nodal treatment . thus , 5 patients were treated with ibt alone and rest 5 patients were treated with combination of ebrt and ibt . for combined treatment , we preferred to perform ibt implant ahead of ebrt as the tumor is well demarcated and the subsequent ebrt course might cause acute inflammation of the local area . patient characteristics median disease free interval was 21 months ( range 7 - 48 months ) summary of treatment and clinical outcome rec . endometrial , rt  radiation therapy , ebrt  external beam radiation therapy , ibt  interstitial brachytherapy , icrt  intracavitary radiation therapy , ned  no evidence of disease after pre - anesthetic evaluation , all patients were hospitalized one day prior to the procedure . the implant procedure was done under spinal anesthesia . after inserting the foley catheter into the bladder , thorough assessment of the tumor dimensions the area to be implanted included gross tumor plus a margin of at least 5 mm . a 2 - 3 plane free - hand implant was performed depending on the implant area . 16-g stainless steel needles along with trocars were inserted manually without using any template ( figure 2a ) . trans - vaginal ultrasonography was used in some patients to guide the needle insertion . in order to avoid close proximity of the needles to urethra and urethral injury , the intra - planar and inter - planar distance was usually kept between 0.8 - 1.2 cm . then the trocars of the needles were removed and the tails of the plastic catheters having button at one end were negotiated through the hollow needles . subsequently , the needles were removed and replaced by plastic catheters which were fixed with buttons ( figures 2b , 2c , and 2d ) . in patients with lesions near proximal urethra , implant was performed with stainless steel needles having blind ends as it was difficult to negotiate the plastic catheters . a ) shows free hand insertion of the implant needle ; b , c , and d show the negotiation of the plastic catheters through the needle and fixing with buttons a planning ct scan of the implant area was done with slice thickness of 2.5 mm . brachytherapy planning was performed on plato planning system , version 14.1 ( nucletron , an elekta company , elekta ab , stockholm , sweden ) . the clinical target volume ( ctv ) and various organs at risk ( oar ) were contoured . the implant catheters were also marked on each slice in order to reconstruct the catheter length . using step size of 2.5 mm , a plan was generated for prescription dose to the ctv . if needed , both graphic and geometric optimization was done to achieve the best plan . the volumes receiving 100% ( v100 ) and 150% ( v150 ) of the prescribed dose were calculated . after the study period , plans were retrieved to calculate the urethral d0.1cc ( dose received by 0.1 cm of the urethra ) . cumulative dose received by 2.0 cm ( d2cc ) of bladder and rectum was also calculated and expressed as 2 gy - equivalent dose ( eqd2 ) using / ratio of 3 . dose homogeneity index ( dhi ) was calculated using the following formula : dhi = v100-v150v100 
  usually , an hdr dose of 42 gy in 14 fractions , using 3 gy per fraction , over 7 days was prescribed for definitive treatment employing twice daily fractionation schedule . in one patient , dose was modified to 37 gy in 10 fractions over 5 days due to three consecutive holidays towards the end of treatment since our institute does not permit radiation treatment on sundays and national holidays . for ibt boost , the usual dose was 18 - 21 gy in 6 - 7 fractions using 3 gy per fraction ( twice daily fractionation schedule ) . treatment was delivered on hdr remote after loading brachytherapy unit ( nucletron , an elekta company , stockholm , sweden ) using ir radioactive source with initial activity of 10 ci for treatment delivery . foley catheter was removed 5 - 7 days after the implant removal to prevent the contamination of the local area by urine . it was planned 2 - 3 weeks after the ibt boost to encompass the primary disease , inguinal nodes , and external/ internal iliac nodes . two anteroposterior - posteroanterior ( ap - pa ) fields were used with wide ap field and narrow pa field . the superior border was kept at l5-s1 level and inferior border at 2.0 cm below the lower extent of the disease . lateral borders anteriorly were placed to cover the inguinal regions and posteriorly placed 2 cm lateral to pelvic inlet . electron fields were used to supplement the dose to inguinal nodes . usually , a dose of 45 - 50 gy in 1.8 gy daily fractions was prescribed but a lower dose ( 36 gy ) was preferred for post - irradiation recurrent cases . initially , monthly follow up was done for the first 6 months and then every 3 months till 2 years . clinical examination was performed at every visit and appropriate imaging was advised whenever there was a suspicion of recurrence in the inguinal or pelvic region . all the recurrences were histopathologically proven by either biopsy or aspiration cytology examination . local recurrence rest of the recurrences were labeled as regional ( inguinal or pelvic region ) or distant . early and late toxicities were assessed and recorded as per radiation therapy oncology group ( rtog ) morbidity criteria . toxicities observed between the date of implant and the 3 month after the completion of the treatment was defined as early , and beyond 3 months it was classified as late . after pre - anesthetic evaluation , all patients were hospitalized one day prior to the procedure . the implant procedure was done under spinal anesthesia . after inserting the foley catheter into the bladder , thorough assessment of the tumor dimensions the area to be implanted included gross tumor plus a margin of at least 5 mm . a 2 - 3 plane free - hand implant was performed depending on the implant area . 16-g stainless steel needles along with trocars were inserted manually without using any template ( figure 2a ) . trans - vaginal ultrasonography was used in some patients to guide the needle insertion . in order to avoid close proximity of the needles to urethra and urethral injury , the intra - planar and inter - planar distance was usually kept between 0.8 - 1.2 cm . then the trocars of the needles were removed and the tails of the plastic catheters having button at one end were negotiated through the hollow needles . subsequently , the needles were removed and replaced by plastic catheters which were fixed with buttons ( figures 2b , 2c , and 2d ) . in patients with lesions near proximal urethra , implant was performed with stainless steel needles having blind ends as it was difficult to negotiate the plastic catheters . a ) shows free hand insertion of the implant needle ; b , c , and d show the negotiation of the plastic catheters through the needle and fixing with buttons a planning ct scan of the implant area was done with slice thickness of 2.5 mm . brachytherapy planning was performed on plato planning system , version 14.1 ( nucletron , an elekta company , elekta ab , stockholm , sweden ) . the clinical target volume ( ctv ) and various organs at risk ( oar ) were contoured . the implant catheters were also marked on each slice in order to reconstruct the catheter length . using step size of 2.5 mm , if needed , both graphic and geometric optimization was done to achieve the best plan . the volumes receiving 100% ( v100 ) and 150% ( v150 ) of the prescribed dose were calculated . after the study period , plans were retrieved to calculate the urethral d0.1cc ( dose received by 0.1 cm of the urethra ) . cumulative dose received by 2.0 cm ( d2cc ) of bladder and rectum was also calculated and expressed as 2 gy - equivalent dose ( eqd2 ) using / ratio of 3 . dose homogeneity index ( dhi ) was calculated using the following formula : dhi = v100-v150v100 
  usually , an hdr dose of 42 gy in 14 fractions , using 3 gy per fraction , over 7 days was prescribed for definitive treatment employing twice daily fractionation schedule . in one patient , dose was modified to 37 gy in 10 fractions over 5 days due to three consecutive holidays towards the end of treatment since our institute does not permit radiation treatment on sundays and national holidays . for ibt boost , the usual dose was 18 - 21 gy in 6 - 7 fractions using 3 gy per fraction ( twice daily fractionation schedule ) . treatment was delivered on hdr remote after loading brachytherapy unit ( nucletron , an elekta company , stockholm , sweden ) using ir radioactive source with initial activity of 10 ci for treatment delivery . foley catheter was removed 5 - 7 days after the implant removal to prevent the contamination of the local area by urine . it was planned 2 - 3 weeks after the ibt boost to encompass the primary disease , inguinal nodes , and external/ internal iliac nodes . two anteroposterior - posteroanterior ( ap - pa ) fields were used with wide ap field and narrow pa field . the superior border was kept at l5-s1 level and inferior border at 2.0 cm below the lower extent of the disease . lateral borders anteriorly were placed to cover the inguinal regions and posteriorly placed 2 cm lateral to pelvic inlet . electron fields were used to supplement the dose to inguinal nodes . usually , a dose of 45 - 50 gy in 1.8 gy daily fractions was prescribed but a lower dose ( 36 gy ) was preferred for post - irradiation recurrent cases . initially , monthly follow up was done for the first 6 months and then every 3 months till 2 years . clinical examination was performed at every visit and appropriate imaging was advised whenever there was a suspicion of recurrence in the inguinal or pelvic region . all the recurrences were histopathologically proven by either biopsy or aspiration cytology examination . local recurrence ( lr ) rest of the recurrences were labeled as regional ( inguinal or pelvic region ) or distant . early and late toxicities were assessed and recorded as per radiation therapy oncology group ( rtog ) morbidity criteria . toxicities observed between the date of implant and the 3 month after the completion of the treatment was defined as early , and beyond 3 months it was classified as late . two of the 5 patients in the combined therapy group had interruption of 3 - 5 days during ebrt due to moist desquamation of the skin in the perineal area . for all patients , dhi ranged from 0.64 - 0.88 with a median of 0.67 . figure 3 demonstrates the ct based brachytherapy planning of a patient showing isodose distribution . 
  computed tomography scan based brachytherapy planning showing isodose distribution in a tumor implanted with 9 catheters in three planes . anteriorly foley 's catheter can also be seen for urethral demarcation details of brachytherapy represents eqd2 , which includes dose from previous rt dhi  dose homogeneity index , gy gray , v90  volume receiving 90% of prescribed dose , v100  volume receiving 100% of prescribed dose , v115  volume receiving 115% of prescribed dose , v150  volume receiving 150% of prescribed dose , d0.1cc urethra  dose received by 0.1 cm of urethra , d2cc bladder  dose received by 2 cm of bladder , d2cc rectum  dose received by 2 cm of rectum , eqd2  equivalent dose in 2 gy fractions median follow up was 25 months ( 4 - 74 months ) . as shown in table 2 , six patients were disease free at their last follow up . four patients developed recurrence : 2 at inguinal nodes , 1 at local site , and 1 at both local as well as inguinal nodes . therefore , local recurrence rate and nodal recurrence rate was 20% and 30% , respectively . one patient with local recurrence only was effectively salvaged by surgery while remaining 3 patients with nodal failure eventually died of their disease . moist desquamation was the commonest acute toxicity observed around 2 weeks in all 5 patients treated by ibt alone , which healed within 4 weeks time . two of the 5 patients treated by combined therapy developed acute grade iii skin reactions in the inguinal region . this was managed by interrupting the treatment for 5 - 7 days and by giving them narcotic analgesics and antibiotics . two of the ibt alone patients had fibrosis of the anterior vaginal wall adjacent to the implanted area but it was asymptomatic . additionally , these two patients had chronic dysuria but none of them required urethral dilatation or any other active intervention . one patient had delayed grade ii proctitis , which was managed by often use of laxatives , hematinic , and steroid enemas . median follow up was 25 months ( 4 - 74 months ) . as shown in table 2 , six patients were disease free at their last follow up . four patients developed recurrence : 2 at inguinal nodes , 1 at local site , and 1 at both local as well as inguinal nodes . therefore , local recurrence rate and nodal recurrence rate was 20% and 30% , respectively . one patient with local recurrence only was effectively salvaged by surgery while remaining 3 patients with nodal failure eventually died of their disease . moist desquamation was the commonest acute toxicity observed around 2 weeks in all 5 patients treated by ibt alone , which healed within 4 weeks time . two of the 5 patients treated by combined therapy developed acute grade iii skin reactions in the inguinal region . this was managed by interrupting the treatment for 5 - 7 days and by giving them narcotic analgesics and antibiotics . two of the ibt alone patients had fibrosis of the anterior vaginal wall adjacent to the implanted area but it was asymptomatic . additionally , these two patients had chronic dysuria but none of them required urethral dilatation or any other active intervention . one patient had delayed grade ii proctitis , which was managed by often use of laxatives , hematinic , and steroid enemas . although some reports are available in the literature , most of them elaborate either on pathological [ 2 , 3 ] or radiological [ 7 , 8 ] aspects . our present study was aimed to explore the role of hdr - ibt in female puc . to the best of our knowledge , ours is the first report , which deals with the role of hdr - ibt in female puc . the report by kathryn greven   comprises patients with recurrent puc and none with primary puc . the results of our study have shown that hdr - ibt is a very effective treatment for female puc . we observed a local control rate of 80% and locoregional control rate of 60% in our series . our delayed grade i - ii complication rate of 30% is within acceptable limits , keeping in mind that 5 out of 10 patients received re - irradiation . greven   reported a series of 10 consecutive women with recurrent lesions from cancer of cervix ( 3 patients ) and endometrium ( 7 patients ) . of them , 4 patients were treated with template based low dose rate ( ldr ) ibt with dose ranging from 40 - 50 gy . remaining 6 patients were treated with combination of ebrt ( 39 - 50 gy ) and ldr - ibt ( 20 - 38 gy ) . the total doses to the tumor for patients who had received previous rt ranged from 40 - 65 gy and 65 - 75 gy for those who received upfront rt . with a median follow up of 34 months ( range 1 - 64 months ) , all patients had achieved local control of the sub - urethral disease at the time of last follow - up . one patient developed a late radiation related complication ( recto - vaginal fistula ) , which required colostomy . the author concluded that recurrent endometrial and cervical cancer in the sub - urethral area show excellent local control with treatment that incorporates ibt . since greven 's study   is the only published study evaluating the role of ibt in female puc , it is worth comparing with our study . apparently , greven 's study   has shown superior local control rate than ours ( 100% vs. 80% ) but this difference may be due to small sample size in both studies . clearly , both studies have shown excellent local control rates . distant metastatic rate was higher in her series than ours ( 40% vs. 0% ) . this may be due to relatively shorter follow up in our study ( 25 vs. 34 months ) , and hence we intend to carefully examine our patients to detect distant metastases during the subsequent follow up visits . regarding treatment related complications , we did not encounter any serious toxicity unlike greven   who noticed recto - vaginal fistula in one patient ( 10% ) , possibly due to higher prescription dose ( 75 gy ) . however , overall grade ii delayed complication rate was 30% in our series . since urethra is in close vicinity to these tumors , it is likely to receive considerable dose during ibt . as there was no dose constraint mentioned for urethra in the literature during our study period , we tried to keep the urethral dose as low as possible without compromising ctv dose . the study by rajagopalan et al . 
  was published after our study period and hence we could not follow the suggestions mentioned in their study . since the authors   observed a correlation between urethral d0.1cc and urethral toxicity , we retrieved the plans of all ten patients from the brachytherapy treatment planning system and determined the urethral d0.1cc . rajagopalan et al .   have reported a higher risk of urethral toxicity in patients with urethral eqd2 of more than 85 gy . the common acute toxicities related to brachytherapy are moist desquamation , local pain , and difficulty during urination because of urethritis . it should be managed with hygienic care , oral antibiotics , and analgesics ( including narcotic analgesics ) and non - steroidal anti - inflammatory drugs . all 5 patients in our series treated with ibt alone developed moist desquamation but it completely resolved within 4 weeks time . we decided the dose of hdr - ibt ( 42 gy using 3 gy per faction ) based on our experience with hdr - ibt in other sites particularly penile cancer . keeping in mind the acceptable toxicity rate in our study , we are considering of escalating the hdr - ibt dose beyond 42 gy to further improve local control rate . due to limited literature , the incidence of regional metastases in female puc is not known . we decided to treat the regional lymph nodes in patients having tumor size of 3 cm or more . this could be due to lack of regional nodal treatment as all the nodal failures were noticed in patients treated with ibt alone . we , therefore , suggest treatment of regional nodes in patients having tumor size more than 2 cm . we preferred free - hand technique as , with template , the position and direction of the needle is fixed . in contrast , free - hand technique permits to change both position and direction of the needle ; hence giving better opportunity to avoid needle injury to urethra and also to improve the dosimetry . the dhi , urethral doses , and avoidance of urethral trauma achieved in our study justifies our free - hand approach . although boost brachytherapy generally follows ebrt for vast majority of cancers , we preferred to perform boost ahead of ebrt for multiple reasons . the sizable tumor itself displaces the normal organs like urethra and vaginal mucosa . on the contrary , after ebrt tumor might show complete or near complete disappearance and therefore difficult to implant . secondly , ebrt if delivered first , might delay the brachytherapy implant due to acute toxicity since perineum is a sensitive area . recently , large doses delivered in quick time ( for example in stereotactic body radiation therapy ) have shown favorable biological effects by inciting immunogenic responses . on the other hand , upfront brachytherapy boost might delay the ebrt and increase the risk of disease progression at regional site . such risk is not robust in female puc since its regional behavior is not well known . greven   had suggested exploring the role of systemic therapy in view of high metastatic rate observed in his series . this aspect is worth exploring in future trials especially in patients with larger and recurrent lesions . even though urethral cancer might have different biological behavior as compared to female puc , experience of brachytherapy for treatment of urethral cancer might be helpful [ 13 , 14 ] . of the 34 patients , 5 received brachytherapy , 14 ebrt only , and 15 a combination of ebrt and brachytherapy . the median dose to the primary tumor delivered by ebrt was 50 gy versus 65 gy for ebrt and brachytherapy . one of the main finding of this study was a significant improvement in local control attributable to the use of brachytherapy . for patients treated with brachytherapy alone or combined with ebrt , the local relapse free rate was 77% compared with 32% for patients treated with ebrt alone . the beneficial effect of brachytherapy was most prominently seen in patients with bulky primary disease . the authors   hypothesized that brachytherapy confers an independent improvement in local tumor control , probably as a result of the higher radiation dose that can safely be delivered . ours is the first study exploring the role of hdr - ibt in female puc . we realize the limitations of our study : 1 ) small sample size , 2 ) mixed population of patients ( primary and recurrent ) , and 3 ) diverse treatment in the form of primary vs. re - irradiation . yet , our study is an important addition to the literature highlighting the technical feasibility , clinical safety , and efficacy of hdr - ibt in female puc .
purposeperi - urethral cancer ( puc ) in females is a rare malignancy . 
 surgery is not usually contemplated due to associated morbidity . 
 radiation therapy ( rt ) can be employed in the form of interstitial brachytherapy ( ibt ) alone for early lesions , and external beam radiation therapy ( ebrt ) with or without ibt for advanced lesions . 
 we report our first experience in the literature to evaluate the role of high - dose - rate ( hdr ) ibt in female puc.material and methodsbetween 2008 and 2013 , 10 female patients with puc ( 5 primary and 5 recurrent ) were treated with hdr - ibt with or without ebrt at our center . 
 size of the lesion ranged from 1.5 cm to 5.0 cm . 
 a 2 - 3 plane free - hand implant was performed using plastic catheters . 
 the prescribed dose of hdr - ibt was 42 gy in 14 fractions for brachytherapy alone ( 5 patients ) , and 18 - 21 gy for the boost along with ebrt ( 5 patients ) . 
 patients were followed up regularly for assessment of disease control and toxicity.resultsat a median follow up of 25 months , six patients were disease free at their last follow up . 
 four patients developed recurrence : 2 at inguinal nodes , 1 at local site , and 1 at both local as well as inguinal nodes . 
 moist desquamation was the commonest acute toxicity observed in all 5 patients treated with ibt alone , which healed within 4 weeks time . 
 overall , grade ii delayed complication rate was 30%.conclusionsthough small sample size , the results of our study have shown that hdr - ibt provides good loco - regional control with acceptable toxicity for female puc .