Radiotherapy and Oncology 117 (2015) 262269Contents lists available at ScienceDirect

Radiotherapy and Oncology

journal homepage: www.thegreenjournal .comIodine-125 brachytherapyUrethral and bladder dosimetry of total and focal salvage Iodine-125prostate brachytherapy: Late toxicity and dose constraintshttp://dx.doi.org/10.1016/j.radonc.2015.08.0180167-8140/ 2015 Elsevier Ireland Ltd. All rights reserved.

Corresponding author at: University Medical Center Utrecht, Department ofRadiotherapy, HP. Q00.118, Heidelberglaan 100, 3584CX Utrecht, The Netherlands.

E-mail address: M.Peters-10@umcutrecht.nl (M. Peters).Max Peters a,, Jochem van der Voort van Zyp a, Carel Hoekstra b, Hendrik Westendorp b,Sandrine van de Pol b, Marinus Moerland a, Metha Maenhout a, Rob Kattevilder b, Marco van Vulpen a

aDepartment of Radiation Oncology, University Medical Center Utrecht; and bRadiotherapeutic Institute RISO, Deventer, The Netherlands

a r t i c l e i n f o a b s t r a c tArticle history:Received 9 April 2015Received in revised form 22 July 2015Accepted 17 August 2015Available online 5 September 2015

Keywords:Focal salvageTotal salvageProstate cancerI125 brachytherapyDosimetryGU toxicityIntroduction: Salvage Iodine-125 brachytherapy (I-125-BT) constitutes a curative treatment approach forpatients with organ-confined recurrent prostate cancer after primary radiotherapy. Currently, focal sal-vage (FS) instead of whole-gland or total salvage (TS) is being investigated, to reduce severe toxicity asso-ciated with cumulative radiation dose. Differences in urethral and bladder dosimetry and constraints toreduce late (>90 days) genitourinary (GU) toxicity are presented here.Materials and methods: Dosimetry on intraoperative ultrasound (US) of 20 FS and 28 TS patients was com-pared. The prostate, bladder, urethra and bulbomembranous (BM) urethra were delineated. Toxicity wasassessed using the CTCAE version 4.0. Dose constraints to reduce toxicity in TS patients were evaluatedwith receiver operating characteristic (ROC) analysis.Results: FS I-125 BT significantly reduces bladder and urethral dose compared to TS. Grade 3 GU toxicityoccurred once in the FS group. For TS patients late severe (Pgrade 3) GU toxicity was frequent (38% in thetotal 61 patients and 56% in the 27 analyzed patients). TS patients with Pgrade 3 GU toxicity showedhigher bladder D2 cc than TS patients without toxicity (median 43 Gy) (p = 0.02). The urethral V100was significantly higher in TS patients with several toxicity profiles:Pgrade 3 urethral strictures,Pgrade2 urinary retention and multiple Pgrade 2 GU toxicity events. Dose to the BM urethra did not show arelation with stricture formation. ROC-analysis indicated a bladder D2 cc

M. Peters et al. / Radiotherapy and Oncology 117 (2015) 262269 263Materials and methods

Patients

The institutional review board approved this analysis. FromMarch 2009 to October 2012, 20 FS I-125-BT procedures were per-formed in the University Medical Centre Utrecht (UMCU). Therecurrent lesion was defined by correlating results from multi-parametric (mp-)MRI and systematic transrectal biopsies. MRI-sequences consisted of T1 and T2-weighted, dynamic contrastenhanced (DCE) and diffusion weighted imaging (DWI). TheT2-weighted MRI delineations were fused with the intraoperativeultrasound and the gross tumour volume (GTV) delineations man-ually adapted with treatment margins expanded up to half of theprostate. No specific margins were adopted for this expansion.The recurrent GTV was prescribed P145 Gy, while the rest of theprostate was not treated. Selection, procedural details and out-comes have been described previously [4]. Furthermore, 62patients were treated with TS I-125-BT in the UMCU and the Radio-therapeutic Institute RISO, Deventer, the Netherlands, fromDecember 2001 to April 2010. In both centres, the prostate withoutmargin was treated with P145 Gy. Images and dosimetry wereanalyzed with the available brachytherapy planning software:Sonographic Planning of Oncology Treatment (SPOT) or OnCentraProstate (OCP) (Nucletron BV, Veenendaal, the Netherlands) inthe UMCU. RISO patients were analyzed using VariseedTM version8 (Varian Medical Systems, Palo Alto, CA). Amersham Health(model 6711) or IBt model 1251L stranded seeds were used inthe RISO patients and Isotron model 130.002 loose seeds (125IselectSeedTM seeds) in UMCU patients.

Delineations and dosimetry

In SPOT and OCP, ultrasound (US)-delineations were performedevery 2.5 mm, in Variseed every 5 mm. The sagittal, transverse andcoronal imaging planes were used. The prostate, GTV (FS patients),bladder, prostatic urethra, peri-apical urethra and bulbomembra-nous (BM) urethra delineations were re-evaluated by two indepen-dent radiation-oncologists (CH, JVZ) before assessment of toxicity.For uniformity in urethral volume, delineations were performed5 mm above the base and 5 mm below the prostatic apex, with adiameter of 5 mm. A Foley-catheter allowed adequate delineation.The peri-apical part of the urethra was delineated 5 mm aboveand below the prostatic apex [11]. CT-based dosimetry was ana-lyzed around the postoperative period (CT1) and after 30 days(CT30, excluding the urethra since it was not clearly visible due toearlier removal of the catheter), and compared to intraoperativedosimetry. CT1 scans were made either intra-operatively (C-armwith cone-beam CT for RISO-patients) or 1 day post-implantation(UMCU patients). Six UMCU patients had CT-scans within 5 hpost-implantation. Delineations were done every 23 mm on CT.The BM urethra was delineated on US and CT1 extending 15 mmfrom the apex. Tumour location in FS patients could have influencedbladder dosimetry. Bladder dosimetry between patients with basalperipheral recurrences and with mid prostate or apical peripheralrecurrences was therefore compared. Dose constraints for primaryprostate BT from the ABS and ESTRO were used [68], supple-mented with parameters from the literature and institutionalguidelines [914]. Parameters evaluated in the literature wereapplied to the bladder [9,10]. For the urethra, the minimum doseto most irradiated 0.01 cc (D0.01 cc) was regarded as maximal dose[15]. The 100% dose corresponds to the prescription level of 145 Gy.

Toxicity

After dosimetry assessment, the primary researcher (MP) ini-tially scored toxicity using the common terminology criteria foradverse events (CTCAE) version 4.0, after which two independentradiation oncologists (CH and JVZ) separately evaluated thesescores. Late toxicitywas defined as occurring >90 days after salvage.The CTCAE-4 defines severe GU toxicity (Pgrade 3) as the need forelective operative/endoscopic intervention. Grade 4 GU toxicityencompasses a life-threatening adverse event, requiring immediateintervention or ICU hospitalization. Grade 2 toxicity is generallydefined as (moderate) symptoms requiring local only or non-invasive interventions, except for retention, where grade 2 includessuprapubic catheter placement. Grade 1 toxicity was not assessed.Statistical analysis

Continuous variables with a skewed distribution, most impor-tantly dosimetry parameters, are presented as medians and ranges.Normally distributed data are presented as mean SD. Differencesbetween skewed data were assessed with a MannWhitney U testand in normally distributed data with an independent samples t-test. Differences in the US and CT-based dosimetry within patientswere tested with aWilcoxon signed-rank test. Categorical variableswere compared using a Pearsons v2-test and a Fishers exact test ifthe frequency in a cell was

Table 1Baseline characteristics of the study populations.

Variable FS (n = 20) TS (n = 28) p

Mean (SD) age at salvage, years 69 (5.0) 69 (5.1)Primary therapyI-125 brachytherapy, 145 Gy 7 (35%) 6 (21%)EBRT, 64.4 Gy, 28 fractions 0 (0%) 14 (50%)

Table 2Dosimetry data for the focal and total salvage treatment plans.

Organ Variable TS group (n = 28) FS group (n = 20) Primary constraintsa p-Value

Prostate D90 (Gy) 167 (154200) NA P145 Gy (TS)V100 (%) 98 (92100) 44 (2557) P95% of CTV

Fig. 1. Urethral (= yellow) D10 difference for TS (A) compared FS (B). The urethral D10 in A was 270 Gy versus 100 Gy in B.

Table 3Dose reductions for different toxicity profiles.

Toxicity type Toxicity presentMedian (range)

Toxicity absentMedian (range)

Median reduction (Gy/cc) p-Value

Pgrade 3 GUBladder D2 cc (Gy) 114 (77144) 71 (33147) 43 0.02

Pgrade 3 urethral stricturesProstatic urethraVolume (cc) 0.71 (0.500.93) 0.68 (0.510.78) 0.03 0.04V100 (cc) 0.59 (0.430.90) 0.51 (0.290.75) 0.08 0.05

Pgrade 2 urethral stricturesProstatic urethraVolume (cc) 0.74 (0.500.93) 0.64 (0.510.78) 0.10

Fig. 2. On the left: Urethral V100 differences for late GU toxicity. + denotes toxicity present, absent. A: Pgrade 3 urethral strictures at every location; B: Pgrade 2 urethralstrictures at every location; C: Pgrade 2 urinary retention; D: multiple Pgrade 2 GU toxicity events. On the right: Difference in bladder D2 cc between patients with(+) andwithout() late Pgrade 3 GU toxicity.

Table 4ROC analysis of the bladder D2 cc and urethral V100 for late GU toxicity.

Variable AUC 95% CI p-Value Restriction Clinical recommendation

Bladder D2 cc, PGr 3 0.76 0.560.96 0.02 69 Gy

268 Salvage Iodine-125 prostate brachytherapy: late genitourinary toxicity and dose constraintsGU toxicity in up to 47% of cases, averaging around 17%[1,2,4,16,17]. Dose escalation in primary IMRT for prostate cancercould further increase the dose to the urethra and bladder base[18,19]. Dose constraints for the salvage setting are therefore ofvital importance and are probably more strict than the constraintsfor the primary setting.

Urethral constraints are currently not comprehensively defined[6,7]. The restrictions for primary BT set by the ABS and ESTRO(D10 and D30) were often exceeded in TS patients. These restric-tions are doses to relative volumes and therefore dependent onthe delineated volume. Absolute parameters (e.g. V100 andD0.01 cc) were therefore analyzed as well. Here, the urethralV100 was consistently larger in patients with different toxicity pat-terns. The V100 is associated with IPSS resolution in primary BT[14]. The ABS mentions the V150 as an important dosimetryparameter as well [6,8]. However, because of the small volumesreceiving 150% dose in these salvage patients, no relation with tox-icity could be assessed.

The V100 urethral constraint of 0.40 cc seems to be the bestestimate to prevent a variety of late GU toxicity, including urinarystrictures, retention and multiple Pgrade 2 toxicity events. Thisrestriction was met in 4 (14%) TS patients and all 20 FS patients.

These findings should be interpreted with care. First, the ROC-analyses were performed on small groups. The wide 95%-confidence intervals of the AUC are an indication of the relativelylow precision. ROC-analysis was performed on TS patients due tobaseline differences between the two salvage cohorts (especiallyprimary radiation dose and method). Dose restriction based onboth TS and FS patients are more precise, but would be based ongroups unequally distributed in prognostic determinants for lateGU toxicity. A multivariable prognostic model based on morepatient data and more events could separately assess the indepen-dent influence of several factors on toxicity.

Second, the urethra in this study was delineated with a speci-fied diameter of 5 mm. Other delineated volumes might lead to adifferent V100 constraint. The restrictions found in this study areprobably only applicable to this specific delineation procedure.

In addition, the Foley catheter distorts urethral morphology.Urethral volume is underestimated and the morphology is signifi-cantly different when visualized using aerated gel. The post-implant urethral angulation can increase the actual received dose[20]. Thus, the correlation between urethral US and CT30-dosimetry is unknown. Studies investigating this relationship oftenestimate the urethral position [21,22]. However, delineations onthe CT30 based on the geometrical center have been found to beunreliable [23]. Therefore, the amount of misclassification of ure-thral dose on CT30 when using interactive catheter based planningremains unknown in this study. On the other hand, misclassifica-tion of dosimetry is possibly non-differential (i.e. on average thesame for all patients), which could add to the validity of intraoper-ative restrictions.

Lastly, it seems dosimetry for the urethra and bladder did notchange significantly on CT1 (and bladder CT30) for TS patients. Thiscould be an indication of the relative noncompliance of these struc-tures in the salvage setting (due to fibrosis), thereby potentiallymaking the intraoperative US-based dosimetry a valid method tobase dosimetry restrictions on. In FS patients, the US-based D2 ccfor the bladder seems to be maximally 26 Gy underestimated. Stillonly 3 FS patients exceeded the proposed 70 Gy restriction, com-pared to 2 based on intraoperative US-dosimetry.

There was no relation between peri-apical urethral dose andstricture formation. The dose to the peri-apical and BM part ofthe urethra was significantly reduced in the FS group (up to>100 Gy). This could suggest that FS has potential to reduce the riskof stricture formation. The peri-apical and BM urethra have beenassociated with stricture formation in other studies [1113]. Vary-ing delineations for the BM urethra were used in these cohorts, forexample a length of 10, 15 or 20 mm below the prostatic apex[12,13]. Because the 15 mm-BM urethra could be delineated in just8 patients (accounting for 3 strictures Pgrade 2) in the TS groupsdue to insufficient US scan length, a difference could not beassessed between dosimetry parameters in stricture and non-stricture patients. When strictures at every location were takentogether, the V100 of the prostatic urethra seems to provide a use-ful restriction.

A somewhat unexpected outcome is that almost all bladderdosimetry parameters showed a significant difference in the stric-ture group, possibly indicating the importance of the bladder neckas a predictor of late GU toxicity [9,10,24].

Regarding urinary retention, no significant relation was seenwith prostatic volume, as has previously been observed [9,14,25].Instead, urethral parameters (both prostatic urethra and the peri-apical part) were increased in retention patients. The relation withretention and urethral dosimetry was not seen in the primary set-ting [9], potentially pointing to an increased sensitivity of the ure-thra in the salvage setting. However, only 6 retention patientscould be analyzed.

There are some additional limitations for the bladder. Theprostate-bladder interface is harder to ascertain on ultrasoundthan on CT-images. Therefore, the dosimetry of the bladder basefound here can be a less precise reflection. The restriction for thebladder (D2 cc

M. Peters et al. / Radiotherapy and Oncology 117 (2015) 262269 269References

[1] Kimura M, Mouraviev V, Tsivian M, Mayes JM, Satoh T, Polascik TJ. Currentsalvage methods for recurrent prostate cancer after failure of primaryradiotherapy. BJU Int. 2010;105:191201. http://dx.doi.org/10.1111/j.1464-410X.2009.08715.x.

[2] Nguyen PL, DAmico AV, Lee AK, SuhWW. Patient selection, cancer control, andcomplications after salvage local therapy for postradiation prostate-specificantigen failure: a systematic review of the literature. Cancer2007;110:141728. http://dx.doi.org/10.1002/cncr.22941.

[3] Hsu CC, Hsu H, Pickett B, et al. Feasibility of MR imaging/MR spectroscopy-planned focal partial salvage permanent prostate implant (PPI) for localizedrecurrence after initial PPI for prostate cancer. Int J Radiat Oncol Biol Phys2013;85:3707. http://dx.doi.org/10.1016/j.ijrobp.2012.04.028; 10.1016/j.ijrobp.2012.04.028.

[4] Peters M, Maenhout M, van der Voort van Zyp JR, et al. Focal salvage iodine-125 brachytherapy for prostate cancer recurrences after primary radiotherapy:a retrospective study regarding toxicity, biochemical outcome and quality oflife. Radiother Oncol 2014;112:7782. doi: S0167-8140(14)00272-2 [pii].

[5] Sasaki H, Kido M, Miki K, et al. Salvage partial brachytherapy for prostatecancer recurrence after primary brachytherapy. Int J Urol 2014;21:5727.http://dx.doi.org/10.1111/iju.12373 [doi].

[6] Crook JM, Potters L, Stock RG, Zelefsky MJ. Critical organ dosimetry inpermanent seed prostate brachytherapy: defining the organs at risk.Brachytherapy 2005;4:18694. http://dx.doi.org/10.1016/j.brachy.2005.01.002.

[7] Salembier C, Lavagnini P, Nickers P, et al. Tumour and target volumes inpermanent prostate brachytherapy: a supplement to the ESTRO/EAU/EORTCrecommendations on prostate brachytherapy. Radiother Oncol 2007;83:310.http://dx.doi.org/10.1016/j.radonc.2007.01.014.

[8] Davis BJ, Horwitz EM, Lee WR, et al. American brachytherapy societyconsensus guidelines for transrectal ultrasound-guided permanent prostatebrachytherapy. Brachytherapy 2012;11:619. http://dx.doi.org/10.1016/j.brachy.2011.07.005 [doi].

[9] Roeloffzen EM, Monninkhof EM, Battermann JJ, van Roermund JG, MoerlandMA, van Vulpen M. Acute urinary retention after I-125 prostate brachytherapyin relation to dose in different regions of the prostate. Int J Radiat Oncol BiolPhys 2011;80:7684. http://dx.doi.org/10.1016/j.ijrobp.2010.01.022 [doi].

[10] Hathout L, Folkert MR, Kollmeier MA, Yamada Y, Cohen GN, Zelefsky MJ. Doseto the bladder neck is the most important predictor for acute and late toxicityafter low-dose-rate prostate brachytherapy: implications for establishing newdose constraints for treatment planning.. Int J Radiat Oncol Biol Phys2014;90:3129.

[11] Earley JJ, Abdelbaky AM, Cunningham MJ, Chadwick E, Langley SE, Laing RW.Correlation between prostate brachytherapy-related urethral stricture andperi-apical urethral dosimetry: a matched case-control study. Radiother Oncol2012;104:18791. http://dx.doi.org/10.1016/j.radonc.2012.06.001 [doi].

[12] Merrick GS, Butler WM, Wallner KE, et al. Risk factors for the development ofprostate brachytherapy related urethral strictures. J Urol 2006;175(4):137680 [doi: S0022-5347(05)00681-6 [pii], discussion 1381].

[13] Merrick GS, Butler WM, Tollenaar BG, Galbreath RW, Lief JH. The dosimetry ofprostate brachytherapy-induced urethral strictures. Int J Radiat Oncol BiolPhys 2002;52:4618.

[14] Neill M, Studer G, Le L, et al. The nature and extent of urinary morbidity inrelation to prostate brachytherapy urethral dosimetry. Brachytherapy2007;6:1739. doi: S1538-4721(07)00210-3 [pii].

[15] Moman MR, van der Poel HG, Battermann JJ, Moerland MA, van Vulpen M.Treatment outcome and toxicity after salvage 125-I implantation for prostatecancer recurrences after primary 125-I implantation and external beamradiotherapy. Brachytherapy 2010;9:11925. http://dx.doi.org/10.1016/j.brachy.2009.06.007.[16] Alongi F, De Bari B, Campostrini F, et al. Salvage therapy of intraprostaticfailure after radical external-beam radiotherapy for prostate cancer: a review.Crit Rev Oncol Hematol 2013. http://dx.doi.org/10.1016/j.critrevonc.2013.07.009; 10.1016/j.critrevonc.2013.07.009.

[17] Parekh A, Graham PL, Nguyen PL. Cancer control and complications of salvagelocal therapy after failure of radiotherapy for prostate cancer: a systematicreview. Semin Radiat Oncol 2013;23:22234. http://dx.doi.org/10.1016/j.semradonc.2013.01.006; 10.1016/j.semradonc.2013.01.006.

[18] Lips IM, van der Heide UA, Haustermans K. Single blind randomized phase IIItrial to investigate the benefit of a focal lesion ablative microboost inprostate cancer (FLAME-trial): study protocol for a randomized controlledtrial. Trials 2011;12. http://dx.doi.org/10.1186/1745-6215-12-255 [255-6215-12-255].

[19] Beckendorf V, Guerif S, Le Prise E, et al. 70 gy versus 80 gy in localized prostatecancer: 5-year results of GETUG 06 randomized trial. Int J Radiat Oncol BiolPhys 2011;80:105663. http://dx.doi.org/10.1016/j.ijrobp.2010.03.049.

[20] Anderson C, Lowe G, Ostler P, et al. I-125 seed planning: an alternative methodof urethra definition. Radiother Oncol 2010;94:249. http://dx.doi.org/10.1016/j.radonc.2009.11.003 [doi].

[21] Stone NN, Hong S, Lo YC, Howard V, Stock RG. Comparison of intraoperativedosimetric implant representation with postimplant dosimetry in patientsreceiving prostate brachytherapy. Brachytherapy 2003;2:1725. http://dx.doi.org/10.1016/S1538-4721(03)00005-9 [doi].

[22] Ishiyama H, Nakamura R, Satoh T, et al. Differences between intraoperativeultrasound-based dosimetry and postoperative computed tomography-baseddosimetry for permanent interstitial prostate brachytherapy. Brachytherapy2010;9:21923. http://dx.doi.org/10.1016/j.brachy.2009.09.007 [doi].

[23] Lee HK, DSouza WD, Yamal JM, et al. Dosimetric consequences of using asurrogate urethra to estimate urethral dose after brachytherapy for prostatecancer. Int J Radiat Oncol Biol Phys 2003;57:35561. doi: S0360301603005832[pii].

[24] Steggerda MJ, van der Poel HG, Moonen LM. An analysis of the relationbetween physical characteristics of prostate I-125 seed implants and lowerurinary tract symptoms: bladder hotspot dose and prostate size are significantpredictors. Radiother Oncol 2008;88:10814. doi: S0167-8140(07)00540-3[pii].

[25] Crook J, McLean M, Catton C, Yeung I, Tsihlias J, Pintilie M. Factors influencingrisk of acute urinary retention after TRUS-guided permanent prostate seedimplantation. Int J Radiat Oncol Biol Phys 2002;52:45360. doi:S036030160102658X [pii].

[26] Eapen L, Kayser C, Deshaies Y, et al. Correlating the degree of needle traumaduring prostate brachytherapy and the development of acute urinary toxicity.Int J Radiat Oncol Biol Phys 2004;59:13924. http://dx.doi.org/10.1016/j.ijrobp.2004.01.041 [doi].

[27] Buskirk SJ, Pinkstaff DM, Petrou SP, et al. Acute urinary retention aftertransperineal template-guided prostate biopsy. Int J Radiat Oncol Biol Phys2004;59:13606. http://dx.doi.org/10.1016/j.ijrobp.2004.01.045 [doi].

[28] Heysek RV, Gwede CK, Torres-Roca J, et al. A dosimetric analysis of unstrandedseeds versus customized stranded seeds in transperineal interstitialpermanent prostate seed brachytherapy. Brachytherapy 2006;5:24450. doi:S1538-4721(06)00242-X [pii].

[29] Saibishkumar EP, Borg J, Yeung I, Cummins-Holder C, Landon A, Crook J.Sequential comparison of seed loss and prostate dosimetry of stranded seedswith loose seeds in 125I permanent implant for low-risk prostate cancer. Int JRadiat Oncol Biol Phys 2009;73:618. http://dx.doi.org/10.1016/j.ijrobp.2008.04.009 [doi].

[30] Moerland MA, van Deursen MJ, Elias SG, van Vulpen M, Jurgenliemk-Schulz IM,Battermann JJ. Decline of dose coverage between intraoperative planning andpost implant dosimetry for I-125 permanent prostate brachytherapy:comparison between loose and stranded seed implants. Radiother Oncol2009;91:2026. http://dx.doi.org/10.1016/j.radonc.2008.09.013 [doi].

http://dx.doi.org/10.1111/j.1464-410X.2009.08715.xhttp://dx.doi.org/10.1111/j.1464-410X.2009.08715.xhttp://dx.doi.org/10.1002/cncr.22941http://dx.doi.org/10.1016/j.ijrobp.2012.04.028;10.1016/j.ijrobp.2012.04.028http://dx.doi.org/10.1016/j.ijrobp.2012.04.028;10.1016/j.ijrobp.2012.04.028http://refhub.elsevier.com/S0167-8140(15)00443-0/h0020http://refhub.elsevier.com/S0167-8140(15)00443-0/h0020http://refhub.elsevier.com/S0167-8140(15)00443-0/h0020http://refhub.elsevier.com/S0167-8140(15)00443-0/h0020http://dx.doi.org/10.1111/iju.12373[doi]http://dx.doi.org/10.1016/j.brachy.2005.01.002http://dx.doi.org/10.1016/j.brachy.2005.01.002http://dx.doi.org/10.1016/j.radonc.2007.01.014http://dx.doi.org/10.1016/j.brachy.2011.07.005[doi]http://dx.doi.org/10.1016/j.brachy.2011.07.005[doi]http://dx.doi.org/10.1016/j.ijrobp.2010.01.022[doi]http://refhub.elsevier.com/S0167-8140(15)00443-0/h0050http://refhub.elsevier.com/S0167-8140(15)00443-0/h0050http://refhub.elsevier.com/S0167-8140(15)00443-0/h0050http://refhub.elsevier.com/S0167-8140(15)00443-0/h0050http://refhub.elsevier.com/S0167-8140(15)00443-0/h0050http://dx.doi.org/10.1016/j.radonc.2012.06.001[doi]http://refhub.elsevier.com/S0167-8140(15)00443-0/h0060http://refhub.elsevier.com/S0167-8140(15)00443-0/h0060http://refhub.elsevier.com/S0167-8140(15)00443-0/h0060http://refhub.elsevier.com/S0167-8140(15)00443-0/h0065http://refhub.elsevier.com/S0167-8140(15)00443-0/h0065http://refhub.elsevier.com/S0167-8140(15)00443-0/h0065http://refhub.elsevier.com/S0167-8140(15)00443-0/h0070http://refhub.elsevier.com/S0167-8140(15)00443-0/h0070http://refhub.elsevier.com/S0167-8140(15)00443-0/h0070http://dx.doi.org/10.1016/j.brachy.2009.06.007http://dx.doi.org/10.1016/j.brachy.2009.06.007http://dx.doi.org/10.1016/j.critrevonc.2013.07.009;10.1016/j.critrevonc.2013.07.009http://dx.doi.org/10.1016/j.critrevonc.2013.07.009;10.1016/j.critrevonc.2013.07.009http://dx.doi.org/10.1016/j.semradonc.2013.01.006;10.1016/j.semradonc.2013.01.006http://dx.doi.org/10.1016/j.semradonc.2013.01.006;10.1016/j.semradonc.2013.01.006http://dx.doi.org/10.1186/1745-6215-12-255http://dx.doi.org/10.1016/j.ijrobp.2010.03.049http://dx.doi.org/10.1016/j.radonc.2009.11.003[doi]http://dx.doi.org/10.1016/j.radonc.2009.11.003[doi]http://dx.doi.org/10.1016/S1538-4721(03)00005-9[doi]http://dx.doi.org/10.1016/S1538-4721(03)00005-9[doi]http://dx.doi.org/10.1016/j.brachy.2009.09.007[doi]http://refhub.elsevier.com/S0167-8140(15)00443-0/h0115http://refhub.elsevier.com/S0167-8140(15)00443-0/h0115http://refhub.elsevier.com/S0167-8140(15)00443-0/h0115http://refhub.elsevier.com/S0167-8140(15)00443-0/h0115http://refhub.elsevier.com/S0167-8140(15)00443-0/h0120http://refhub.elsevier.com/S0167-8140(15)00443-0/h0120http://refhub.elsevier.com/S0167-8140(15)00443-0/h0120http://refhub.elsevier.com/S0167-8140(15)00443-0/h0120http://refhub.elsevier.com/S0167-8140(15)00443-0/h0120http://refhub.elsevier.com/S0167-8140(15)00443-0/h0125http://refhub.elsevier.com/S0167-8140(15)00443-0/h0125http://refhub.elsevier.com/S0167-8140(15)00443-0/h0125http://refhub.elsevier.com/S0167-8140(15)00443-0/h0125http://dx.doi.org/10.1016/j.ijrobp.2004.01.041[doi]http://dx.doi.org/10.1016/j.ijrobp.2004.01.041[doi]http://dx.doi.org/10.1016/j.ijrobp.2004.01.045[doi]http://refhub.elsevier.com/S0167-8140(15)00443-0/h0140http://refhub.elsevier.com/S0167-8140(15)00443-0/h0140http://refhub.elsevier.com/S0167-8140(15)00443-0/h0140http://refhub.elsevier.com/S0167-8140(15)00443-0/h0140http://dx.doi.org/10.1016/j.ijrobp.2008.04.009[doi]http://dx.doi.org/10.1016/j.ijrobp.2008.04.009[doi]http://dx.doi.org/10.1016/j.radonc.2008.09.013[doi]

Urethral and bladder dosimetry of total and fMaterials and methodsPatientsDelineations and dosimetryToxicityStatistical analysis

ResultsPatient characteristics and follow-upDosimetry availabilityLate GU toxicityUS-based TS and FS dosimetryTS dosimetry and GU toxicityNeedles, seeds, primary therapy and GU toxicityUS and CT-based dosimetryROC-analysis

DiscussionConclusionFundingConflict of interestReferences