though radical surgery was the usually adopted treatment in japan , radiotherapy with or without chemotherapy began to be selected for many patients with uterine cervical cancer . notable differences have been observed between american and japanese radiotherapeutic techniques . at most institutions in japan , a midline block was inserted at the latter half of the pelvic external radiation treatment . the total biologically effective dose ( bed ) delivered to the primary lesion in japan was approximately 80% of that in the united states ( 85.5 gy in japan vs. 103 gy in the united states ) . meanwhile , some randomized clinical trials reported a significant improvement in pelvic disease control and survival when concurrent chemotherapy consisting of cisplatin ( cddp)-containing regimens was added to radiotherapy ( rt ) in treating patients with locally advanced cervical cancer [ 24 ] . in our institution , the patients with residual malignant cells detected at the final stage of intracavitary brachytherapy ( icbt ) were treated with boost icbt . the results of this selective boost icbt for cervical cancer in our department were assessed in this retrospective study . patients with cervical cancer treated with primary radical radiotherapy with or without chemotherapy at the university of tokyo hospital between august 2004 and december 2008 were evaluated . a total of 75 patients in the international federation of gynaecology and obsterics ( figo ) stages ib1 ( n = 10 ) , ib2 ( n = 2 ) , iia ( n = 8) , iib ( n = 19 ) , iiia ( n = 3 ) , iiib ( n = 19 ) , iva ( n = 2 ) , ivb ( n = 12 ) were treated . patients with para - aortic lymph node swelling ( n = 12 ) were eligible . patients who underwent external beam radiation therapy ( ebrt ) at other institutions were not excluded . seventeen patients ( 23% ) were treated with radiation therapy ( rt ) alone and 58 patients ( 77% ) were treated with concurrent chemoradiation therapy ( ccrt ) . patient characteristics patients were evaluated with a physical and pelvic examination without anesthesia , routine blood counts , blood chemistry profile , chest radiograph , intravenous urogram , proctoscopy , and cystoscopy . computed tomography ( ct ) scan , magnetic resonance imaging ( mri ) , and positron emission tomography ( pet ) were used for detecting lymphadenopathy and distant metastases . all patients underwent radical radiotherapy as primary treatment for cervical cancer with intent to cure . external - beam radiation therapy ( ebrt ) of whole pelvic irradiation ranged from 30.6 gy for non - bulky stages i or ii to 41.4 gy for bulky stages i or ii , and over stage ii . these regimens were applied in 17 to 22 fractions and whole pelvic irradiation with a midline block from 9.0 gy to 19.8 gy in 6 to 11 fractions ( 1.8 gy fractions from monday to friday ) . whole pelvic irradiation was administered using a linear accelerator with four fields of a 10 mv photon beam ( two anterior - posterior opposed fields , and two lateral opposed fields ) . whole pelvic irradiation with a 4 cm wide midline block was administered using two anterior - posterior opposed fields to decrease the dose to the rectum and the bladder . all patients undergoing three - dimensional ( 3d ) radiation treatment planning were positioned on the couch of the ct simulator in a supine position . the gross tumor volume ( gtv ) consisted of the primary cervical mass of the uterus and metastatic lymph nodes if present . the clinical target volume ( ctv ) included all areas of gross and potentially microscopic disease , and included the upper half of the vagina , parametria , uterus , presacral region , and regional lymph node regions ( common , internal and external iliacs , para - aortic , obturator regions ) . the ctv in the para - aortic region was contiguous with the pelvic lymph node stations and generously encompassed the aorta and the inferior vena cava with at least a 1.5-cm margin . the superior field border was usually a bifurcation of the common iliac artery and the inferior border was usually a tuber of the ischium . for the lateral fields , the anterior margin was the anterior edge of the symphysis or 3 cm in front of the sacral promontory . the posterior margin was the s2s3 interspace , or the posterior border of the uterine cervix assessed by ct for treatment planning plus a 2 cm margin . three to four weeks after starting ebrt , iridium-192 insertions were performed 4 times weekly or twice - weekly . high - dose - rate intracavitary therapy was delivered by placing after - loading applicators ( tandem & two ovoids ) in the uterine cavity and vagina . a manchester system applicator ( nucletron , an elekta company , elekta ab , stockholm , sweden ) was used . the dose distribution was calculated with the ct planning system ( plato planning system , nucletron , an elekta company , elekta ab , stockholm , sweden ) for each individual patient and placement . anterior and posterior vaginal packing was used in an attempt to displace the bladder and rectum from the applicators . high - dose - rate icbt was performed with a dose of 6 gy at point a. doses in icru points in rectum and bladder were within 70% and 80% of the prescription dose at point a. for each case of icbt , pelvic examination was performed with biopsy of the external os of uterus at the third and fourth applications of icbt . biopsies were obtained at a depth of within 5 mm at the external os because of the shape of the device for biopsy . if residual malignant cells were detected , these patients were treated with additional icbt dose of 4.5 gy at the uterine cervix , which was detected by the ct . although additional icbt and biopsy were performed with tandem and ovoids , a cylindrical type applicator was used for additional icbt in case there was a sufficient distance between rectum , bladder , and the uterine cervix . if the judgment on the presence of residual malignant cells was not clear , biopsy at the cervical os was repeated . the treatment was concluded after confirming the absence of residual malignant cells in two consecutive biopsies . all of the 64 patients treated with chemotherapy and concurrent platinum - based chemotherapies were combined with rt . in the cases of early stage ( figo stages ia & ib1 ) , advanced age , poor renal or heart function , or in patients declining chemotherapy , thirty six patients ( 56% ) received tri - weekly cddp or nedaplatin ( 75 - 80 mg / m in a bolus infusion on days 1 , 22 and 43 ) . sixteen patients ( 25% ) received weekly cddp or nedaplatin ( 30 - 40 mg / m in a bolus infusion ) after april 2006 . other patients who were treated only with icbt at our institution received 5fu and cddp ( n = 1 ) , paclitaxel and carboplatin ( n = 1 ) , and cddp by arterial infusion and weekly 5fu / cddp ( n = 1 ) . about these patients , chemotherapy regimens were not specified for two patients ( 3% ) who were treated only with icbt at our institution . the patients were seen every 1 - 3 months for the first year , every 3 - 4 months for the next 2 years , and 3 - 12 months thereafter . follow - up procedures , included pelvic examination , palpation of supraclavicular nodes , cervical papanicolaou smear , and review of serum tumor marker values such as squamous cell carcinoma antigen , carcinoembryonic antigen , and p53 . when central and/or parametrial recurrence was suspected by pelvic examination and/or papanicolaou smear , a biopsy was taken for confirmation . intravenously enhanced chest , abdominal and pelvic cts were performed at least every 6 months . other imaging studies , such as mri , ultrasound bone scintigraphy and pet were not routinely performed . late complications were graded in accordance with the national cancer institute common toxicity criteria ( nci - ctc ) version 3.0 , especially for bladder and bowel complications . statistical analyses were performed using statview dataset file version 5.0j for windows computers . overall survival ( os ) patients with cervical cancer treated with primary radical radiotherapy with or without chemotherapy at the university of tokyo hospital between august 2004 and december 2008 were evaluated . a total of 75 patients in the international federation of gynaecology and obsterics ( figo ) stages ib1 ( n = 10 ) , ib2 ( n = 2 ) , iia ( n = 8) , iib ( n = 19 ) , iiia ( n = 3 ) , iiib ( n = 19 ) , iva ( n = 2 ) , ivb ( n = 12 ) were treated . patients with para - aortic lymph node swelling ( n = 12 ) were eligible . patients who underwent external beam radiation therapy ( ebrt ) at other institutions were not excluded . seventeen patients ( 23% ) were treated with radiation therapy ( rt ) alone and 58 patients ( 77% ) were treated with concurrent chemoradiation therapy ( ccrt ) . patient characteristics patients were evaluated with a physical and pelvic examination without anesthesia , routine blood counts , blood chemistry profile , chest radiograph , intravenous urogram , proctoscopy , and cystoscopy . computed tomography ( ct ) scan , magnetic resonance imaging ( mri ) , and positron emission tomography ( pet ) were used for detecting lymphadenopathy and distant metastases . all patients underwent radical radiotherapy as primary treatment for cervical cancer with intent to cure . external - beam radiation therapy ( ebrt ) of whole pelvic irradiation ranged from 30.6 gy for non - bulky stages i or ii to 41.4 gy for bulky stages i or ii , and over stage ii . these regimens were applied in 17 to 22 fractions and whole pelvic irradiation with a midline block from 9.0 gy to 19.8 gy in 6 to 11 fractions ( 1.8 gy fractions from monday to friday ) . whole pelvic irradiation was administered using a linear accelerator with four fields of a 10 mv photon beam ( two anterior - posterior opposed fields , and two lateral opposed fields ) . whole pelvic irradiation with a 4 cm wide midline block was administered using two anterior - posterior opposed fields to decrease the dose to the rectum and the bladder . all patients undergoing three - dimensional ( 3d ) radiation treatment planning were positioned on the couch of the ct simulator in a supine position . the gross tumor volume ( gtv ) consisted of the primary cervical mass of the uterus and metastatic lymph nodes if present . the clinical target volume ( ctv ) included all areas of gross and potentially microscopic disease , and included the upper half of the vagina , parametria , uterus , presacral region , and regional lymph node regions ( common , internal and external iliacs , para - aortic , obturator regions ) . the ctv in the para - aortic region was contiguous with the pelvic lymph node stations and generously encompassed the aorta and the inferior vena cava with at least a 1.5-cm margin . the superior field border was usually a bifurcation of the common iliac artery and the inferior border was usually a tuber of the ischium . for the lateral fields , the anterior margin was the anterior edge of the symphysis or 3 cm in front of the sacral promontory . the posterior margin was the s2s3 interspace , or the posterior border of the uterine cervix assessed by ct for treatment planning plus a 2 cm margin . three to four weeks after starting ebrt , iridium-192 insertions were performed 4 times weekly or twice - weekly . high - dose - rate intracavitary therapy was delivered by placing after - loading applicators ( tandem & two ovoids ) in the uterine cavity and vagina . a manchester system applicator ( nucletron , an elekta company , elekta ab , stockholm , sweden ) was used . the dose distribution was calculated with the ct planning system ( plato planning system , nucletron , an elekta company , elekta ab , stockholm , sweden ) for each individual patient and placement . anterior and posterior vaginal packing was used in an attempt to displace the bladder and rectum from the applicators . high - dose - rate icbt was performed with a dose of 6 gy at point a. doses in icru points in rectum and bladder were within 70% and 80% of the prescription dose at point a. for each case of icbt , pelvic examination was performed with biopsy of the external os of uterus at the third and fourth applications of icbt . biopsies were obtained at a depth of within 5 mm at the external os because of the shape of the device for biopsy . if residual malignant cells were detected , these patients were treated with additional icbt dose of 4.5 gy at the uterine cervix , which was detected by the ct . although additional icbt and biopsy were performed with tandem and ovoids , a cylindrical type applicator was used for additional icbt in case there was a sufficient distance between rectum , bladder , and the uterine cervix . if the judgment on the presence of residual malignant cells was not clear , biopsy at the cervical os was repeated . the treatment was concluded after confirming the absence of residual malignant cells in two consecutive biopsies . all of the 64 patients treated with chemotherapy and concurrent platinum - based chemotherapies were combined with rt . in the cases of early stage ( figo stages ia & ib1 ) , advanced age , poor renal or heart function , or in patients declining chemotherapy , the treatment was with rt  alone . thirty six patients ( 56% ) received tri - weekly cddp or nedaplatin ( 75 - 80 mg / m in a bolus infusion on days 1 , 22 and 43 ) . sixteen patients ( 25% ) received weekly cddp or nedaplatin ( 30 - 40 mg / m in a bolus infusion ) after april 2006 . other patients who were treated only with icbt at our institution received 5fu and cddp ( n = 1 ) , paclitaxel and carboplatin ( n = 1 ) , and cddp by arterial infusion and weekly 5fu / cddp ( n = 1 ) . about these patients , chemotherapy regimens were not specified for two patients ( 3% ) who were treated only with icbt at our institution . the patients were seen every 1 - 3 months for the first year , every 3 - 4 months for the next 2 years , and 3 - 12 months thereafter . follow - up procedures , included pelvic examination , palpation of supraclavicular nodes , cervical papanicolaou smear , and review of serum tumor marker values such as squamous cell carcinoma antigen , carcinoembryonic antigen , and p53 . when central and/or parametrial recurrence was suspected by pelvic examination and/or papanicolaou smear , a biopsy was taken for confirmation . intravenously enhanced chest , abdominal and pelvic cts were performed at least every 6 months . other imaging studies , such as mri , ultrasound bone scintigraphy and pet were not routinely performed . late complications were graded in accordance with the national cancer institute common toxicity criteria ( nci - ctc ) version 3.0 , especially for bladder and bowel complications . statistical analyses were performed using statview dataset file version 5.0j for windows computers . overall survival ( os ) was calculated from the first date of ebrt . median follow - up time for all 75 patients was 30 months ( range 3.1 - 72.9 months ) . most patients ( n = 65 , 87% ) were diagnosed with squamous cell carcinoma ( sqcc ) . four patients ( 5% ) had adenocarcinoma ( ac ) and six patients ( 8% ) had adenosquamous cell carcinoma ( asc ) . the 2 and 5-year os rates were 75% and 62% , respectively . for css , figure 2 shows the 5-year outcomes of 56% and 83% for the disease free survival ( dfs ) and local disease free survival ( ldfs ) , respectively . overall survival ( os ) and cause specific survival ( css ) curves disease free survival ( dfs ) and local disease free survival ( ldfs ) curves 
 table 2 shows the relationship between additional icbt treatments and figo stages . eighteen patients ( 24% ) out of 75 received one additional icbt and five patients ( 7% ) had two additional icbt . the differences in the number of additional icbt performed among figo stages were not significant ( p = 0.6 ) . among the patients treated with additional icbt , the differences in factors such as : ( ccrt vs. rt alone , figo stage i / ii vs. iii / iv , hemoglobin < 12 mg / ml vs. > 12 mg / ml , age < 60 years vs. > 60 years , sqcc vs. ac vs. asc ) , were also not significant ( table 3 ) . thus , the clinical characteristics listed above of cervical tumors showed no correlation with the additional icbt given in this study . 
  number of additional intracavitary brachytherapy ( icbt ) each figo stage percentage of performing additional intracavitary radiotherapy ( icrt ) late complications were defined as complications that persisted or occurred more than 60 days after treatment . non - hematological toxicities greater than grade 2 occurred in 12 patients ( 16% ) , and were comprised of the following : intestinal obstruction ( n = 1 , grade 3 ) , bloody stool ( n = 7 , grade 3 ) , cystitis ( n = 1 , grade 4 ) , small - intestinal perforation ( n = 3 , grade 4 ) ( table 4 ) . of these , only two patients received one additional icbt ( one grade 3 intestinal obstruction and one grade 3 bloody stool ) ( table 5 ) . the difference in the additional icbt between > grade 3 late toxicity was not significant ( p = 0.8 ) . non - hematological toxicity details of severe ( > grade 2 ) complications fec regimen the 2 and 5-year os rates were 75% and 62% , respectively . for css , the 2- and 5-year rates were 78% and 72% , respectively . figure 2 shows the 5-year outcomes of 56% and 83% for the disease free survival ( dfs ) and local disease free survival ( ldfs ) , respectively . overall survival ( os ) and cause specific survival ( css ) curves disease free survival ( dfs ) and local disease free survival ( ldfs ) curves eighteen patients ( 24% ) out of 75 received one additional icbt and five patients ( 7% ) had two additional icbt . the differences in the number of additional icbt performed among figo stages were not significant ( p = 0.6 ) . among the patients treated with additional icbt , the differences in factors such as : ( ccrt vs. rt alone , figo stage i / ii vs. iii / iv , hemoglobin < 12 mg / ml vs. > 12 mg / ml , age < 60 years vs. > 60 years , sqcc vs. ac vs. asc ) , were also not significant ( table 3 ) . thus , the clinical characteristics listed above of cervical tumors showed no correlation with the additional icbt given in this study . number of additional intracavitary brachytherapy ( icbt ) each figo stage percentage of performing additional intracavitary radiotherapy ( icrt ) late complications were defined as complications that persisted or occurred more than 60 days after treatment . non - hematological toxicities greater than grade 2 occurred in 12 patients ( 16% ) , and were comprised of the following : intestinal obstruction ( n = 1 , grade 3 ) , bloody stool ( n = 7 , grade 3 ) , cystitis ( n = 1 , grade 4 ) , small - intestinal perforation ( n = 3 , grade 4 ) ( table 4 ) . of these , only two patients received one additional icbt ( one grade 3 intestinal obstruction and one grade 3 bloody stool ) ( table 5 ) . the difference in the additional icbt between > grade 3 late toxicity was not significant ( p = 0.8 ) . non - hematological toxicity details of severe ( > grade 2 ) complications fec regimen in 1997 , a randomized controlled trial demonstrated no difference in the survival rates between definitive radiotherapy and surgery for cervical cancer patients in early stages of ib and iia . therefore , radiation therapy may have been considered one of the good options in the treatment of cervical cancer . in the usa , the american brachytherapy society issued radiotherapy guidelines for uterine cervical cancer [ 6 , 7 ] , the gec - estro working group recommended 3d dose - volume parameters for brachytherapy [ 8 , 9 ] , and in japan , the general rules for clinical and pathological study of uterine cervical cancer provided treatment guidelines , including the standard treatment schedule of radiotherapy . since the japanese have a smaller physique than westerners , a local irradiated dose is lower in japan than in the usa . the total biologically effective dose delivered to the primary lesion in japan was reported to be approximately 80% of that in usa ( 85.5 gy and 103 gy , respectively ) . however , our treatment planning centered on increasing radiation dose with the aim of improving local control rate and survival rate . therefore , icbt was added only for cases , in which a poor early treatment reaction was revealed by biopsy when the treatment was concluded in our institution . nevertheless , when the central block was inserted after 40 gy , bed ( a / b = 10 gy ) was 98.7 gy ( eqd2 = 82.9 gy ) , which was not a very high dose when compared with procedures in the usa . the 3 year os for each of the four stages showed the following results : i , 100% ; ii , 73% ; iii , 57% , and iv , 59% . considering that half of the cases were in stages iib & iiib and the small number of patients in the other stages , the outcome was encouraging . notably , for 12 cases in stage ivb with para - aortic lymph node metastases , os at 3 years was 59% and compared favorably with other previous reports ( table 6 ) . local disease - free survival ( ldfs ) showed an effective result of 83% at 5 years ( figure 2 ) . there was no difference in css ( p = 0.9 ) and in ldfs ( p = 0.6 ) in treating with or without additional intracavitary radiotherapy ( icrt ) ( figs . 3 and 4 ) . this result suggests that additional icrt treatment did not exert a deleterious effect on prognosis . it is also clear that additional icrt should not be performed for all patients . cause specific survival : with and without additional intracavitary radiotherapy ( icrt ) local disease free survival : with and without additional intracavitary radiotherapy ( icrt ) survival outcomes due to stage os  overall survival in this study , boost icbt was planned by using ct scan and was performed for the uterine cervix . as the gec - estro recommendations of 2005   described the concepts of gtv , and ctv for brachytherapy , magnetic resonance imaging ( mri ) will decide the residual - gtv for boost icbt on pathological residual tumors . however , not all cases with residual malignant tumors will be detected by mri , especially in those with a small number of residual tumor cells . it is recommended that the combination of image - based therapy and pathological diagnosis be used . the gec - estro recommendations of 2006   reported the data set for 3d image - based cervical cancer brachytherapy for use as a minimum requirement to determine which parameters provide clinically useful information for boost icbt . on the other hand , it was reported that interstitial techniques used in addition to icbt for advanced uterine cervix improved cancer specific survival ( css ) and os . at the three - year point of our study , os showed good outcomes . that study reported 74% for ib , 79% for iib , 45% for iiib , while in our study the results were 100% for stage i , 73% for stage ii , 57% for stage iii , and 59% for stage both studies tried the dose up for local tumors , and that resulted in a better outcome . however , it suggests the local dose up will be able to improve the treatment of advanced cervical carcinoma , this boost treatment has a limited ability to reach the residual tumor extension in cases with asymmetric topography and/or unfavorable topography of the organs at risk . currently accepted optimal or gold - standard method is based on mri guided optimization of application technique and dose distribution and typically includes insertion and loading of interstitial parametrial needles [ 1214 ] . the accumulated incidence of complications at 3 years for  grade 3 was 18% ( fig . additionally , no difference was seen in the complication incidences in those patients with and without additional icrt ( p = 0.8 ) . the decision on performing additional treatment although residual tumor cells may have been recognized in the biopsy , it is also possible that they would have succumbed to the radiation effect without additional treatment . in such a scenario , additional treatment would have constituted an  over treatment  for such cases . moreover , if additional icrt had resulted in good results for the cases with poor prognosis , the lack of differences in css and ldfs when treating with or without additional icrt was not a disappointment . of course the rate of response by the tumor might indicate the need for higher dosage . overall rate without non - hematological complications  grade 2 the reason for the good three year os for figo stage ivb cases in this study as well as the overall good dfs , ldfs , and css , is not clear . it might have been due to the aggressive treatment for advanced stage of cervical carcinoma . this recalls the fact that ebrt with midline block was often used previously in japan , and that radiotherapy protocol had shown favorable results . for example , case number was low , resulting statistical insufficiencies and the ct based technique , utilizing the point a prescription approach , which is somehow outdated in the modern state - of - the - art icrt approaches . additional ct based icrt not using mri guided was performed for cases , in which early local treatment reaction was presumed inadequate . although the local control rate was encouraging , the results for os and css were not significant to support the decision for additional biopsy at the end of treatment . however , the method to perform dose escalation should be examined depending on the treatment response .
purposethis study assessed the trial of boost intracavitary brachytherapy ( icbt ) for the patients of uterine cervical cancer with residual malignant cells detected at the final stage of icbt.material and methodsthis is a retrospective analysis of 75 patients with cervical cancer treated radically with external beam radiotherapy and high - dose - rate intracavitary brachytherapy between august 2004 and december 2008 . 
 eighteen patients ( 24% ) out of 75 received one additional icbt and five patients ( 7% ) had two additional icbt . 
 all 75 patients were retrospectively analyzed . 
 the median follow - up time was 30 months . 
 the median age was 59 years ( range 28 - 85 years ) . 
 there were 12 patients ( 16% ) in stage ib , 27 ( 36% ) stage ii , 22 ( 29% ) stage iii , and 14 ( 19% ) stage iv.resultsthe 5-year overall survival rate was 65% . 
 non - hematological toxicities greater than grade 2 occurred in 12 patients ( 16% ) . of these , only two patients received on additional icbt . 
 no significant difference was found in grade 3 toxicity between patients who did and did not receive additional icbt ( p = 0.8).conclusionsthe method to perform dose escalation should be examined depending on the treatment response .