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Urinary incontinence after high-dose-rate brachytherapy boost treatment for prostate cancer
Brachytherapy
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(2016)
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Urinary incontinence after high-dose-rate brachytherapy boost treatment for prostate cancer Borut Kragelj1,*, Lijana Zaletel-Kragelj2 2
1 Department of Brachytherapy, Institute of Oncology Ljubljana, Ljubljana, Slovenia Department of Public Health, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
ABSTRACT
PURPOSE: To evaluate urinary incontinence (UI) and to elucidate potential risk factors important for the appearance or deterioration of pre-existing UI after high-dose-rate boost treatment of prostate cancer. METHODS AND MATERIALS: The change in grade of UI regarding the state at the start of treatment was assessed in 88 patients, consecutively treated from October 2006 through April 2011 with high-dose-rate brachytherapy of 3 6e7 Gy to 50e50.4 Gy of external-beam radiation. Increase in UI grade was defined as deterioration of UI (DUI). The impact of patients and treatment characteristics on third year prevalence of DUI was analyzed by using binary logistic regression method. RESULTS: At third year, DUI of followup was evidenced in 17/81 (20.9%) patients. It significantly impacted micturition quality ( p 5 0.015) and was associated with D2ccbladder volume (odds ratio [OR]: 1.14; 95% confidence interval [CI]: 1.03e1.26; p 5 0.010), diabetes (OR: 6.73; 95% CI: 1.17e38.56; p 5 0.032), and initial nocturnal micturition frequency (OR: 3.72; 95% CI: 1.03e 13.04; p 5 0.045). Based on a multivariate model, a range of ‘‘safe’’ D2ccbladder volume ðEQD2Þ doses is suggested (no risk factor: 21.9 Gy, frequent initial nocturnal micturition only: 12.0 Gy, diabetes only: 7.6 Gy, both risk factors: no safe dose). CONCLUSIONS: The study featured on urinary bladder base as a risk structure for UI. By taking account of the dose to urinary bladder base in conjunction with diabetes and initial nocturnal micturition frequency, the risk of UI could be reduced. Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Urinary incontinence; High-dose-rate brachytherapy; Prostate cancer
Introduction Urinary incontinence (UI) is one of the adverse effects that may occur after various forms of radical local prostate cancer treatment. It may be a lifelong complication with significant impact on patients’ outcome satisfaction (1). UI can be expected also after the external-beam radiation (EBRT) and high-dose-rate brachytherapy (HDRB) boost treatment (2e9). The reported rates of UI after EBRT þ HDRB are highly variable, and several factors may be implicated for this dispersity of data such as different definitions or different methods of assessment.
Received 9 February 2016; received in revised form 22 March 2016; accepted 23 March 2016. * Corresponding author. Institute of Oncology, Zaloska 2, Ljubljana, Slovenia. Tel.: þ386-1-5879-489; fax: þ386-1-5879-400. E-mail address: [email protected] (B. Kragelj).
In institutional series, the reported incidence of UI is up to 22% (3) with up to 4% rate of UI required the use of pads (4). Higher rates of more pronounced form of UI were reported if quality-of-life questionnaires were used to obtain data (7, 8). In terms of UI, EBRT þ HDRB is comparable to other modes of radiation treatmentdsole EBRT and low-doserate brachytherapy (LDRPB) (5, 7) When compared to radical prostatectomy, EBRT þ HDRB is as advantageous as other forms of radiation treatment (7). However, reported followup of patients after EBRT þ HDRB is short and UI after EBRT þ HDRB, unlike other treatments, seemed to increase with longer observation (7). Clinical and dosimetric parameters as well as critical organs implicated in UI after EBRT þ HDRB are largely unknown. Nevertheless, there exist some studies that provide valuable information. For example, Galalae et al. (10) have identified the relationship between the interval of less than
1538-4721/$ - see front matter Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2016.03.010
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6 months to transurethral resection with a significant increase of UI. However, in general, the rate of UI was very low. Astr€ om et al. (11) and Luo et al. (12) showed basically identical very favorable outcomes of HDR brachytherapy for prostate cancer associated with very low rates of UI and significantly lower vs. EBRT alone. In consequence, the results of these three studies were perfectly in line demonstrating superiority of prostate HDR brachytherapy in terms of radiotherapy-related toxicity in comparison with alternative boost methods. More is known about late-urinary toxicity (LUT) on general. Several dosimetric studies pointed at prostatic urethra as a critical organ (6, 8, 13, 14). LUT is related to either volumes of urethra that received doses higher than the prescribed dose (6, 14) or to high doses received by the small fragments of urethra (8, 13). Similar relation between LUT and the regions that received high doses was shown also for the whole prostate (3, 6, 9, 13). Critical are doses 10e100% higher than the prescribed dose with related volumes. However, generalization of these predictive factors for LUT on UI seems not to be absolutely reliable as at least in some of the aforementioned studies UI represented only a small part of LUT. Aiming at individualizing treatment and improving safety of EBRT þ HDRB, the objective of the study was to define patients’ and treatment’s characteristics that are related specifically to UI. Methods and materials Patients In the followup study, 88 patients, consecutively treated by the author with EBRT þ HDRB at the Institute of Oncology Ljubljana (IOL) in the period 2006e2011, were included. EBRT þ HDRB was primarily offered to patients with intermediate- or high-risk clinically localized or locally advanced prostate cancer (15) and to low-risk patients who refused to get radical prostatectomy, if feasible for brachytherapy. In general, patients were considered eligible for EBRT þ HDRB if ultrasound showed no pubic arch interference, were eligible to undergo regional anesthesia with spinal block, and eligible to perform CT/MRI scan. Treatment characteristics Brachytherapy was performed with the patient in lithotomy position and consisted of TRUS-guided transperineal insertion of 20- or 30-cm-long closed-end plastic needles into the prostate and in selected patients also into the initial part of seminal vesicles, the use of the in-house made template that allows also needle fixation and aerated xylocaine gel in the Foley catheter to improve visibility of urethra. Needles were typically placed into prostate periphery and suburethraly. Finally, cystoscopy was performed with patient in recumbent
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position with extended legs for determining the final position of the tips of needles beneath bladder mucosa. After completion of the implant procedure, CT (slice thickness 1.6 mm) or MRI scan (T2-weighted fast-spin echo paratransversal sequence and fast recovery 3D fast-spin echo sequence with 1 mm isotropic voxels) was acquired for planning purposes. Brachyvision planning system was used for image registration, contouring, and dosimetry. Two planning target volumes (PTVs) were routinely defined: PTV1 encircled the prostate with additional 3-mm margin around the zone of suspected capsular invasion, whereas PTV2 encircled peripheral part of the prostate. When visible on the MRI images, also gross tumor volume was defined and included in the PTV2. Initially, prescribed dose was 21 Gy to PTV1 and 22.5 Gy to PTV2, with 7 Gy and 7.5 Gy per fraction, respectively. Later, the dose was reduced to 18 Gy to PTV1 and 19.5 Gy to PTV2, also given in three fractions. The biologically equivalent doses for PTV1 and accepting an a/b 5 1.5 were 119 Gy and 90 Gy respectively. Implanted fiducial markers (1.2 3e5 mm sized gold seeds) and in most patients CT scan were used to estimate needle shift before the third fraction. Interfraction interval was 6e8 hours. However, in case of excessive overnight needle shift that could not be compensated with extraplanning, an additional implantation was performed for the delivery of the third treatment fraction. Urethra was identified with the urinary catheter. The contour enclosed also the additional 1- to 2-mm margin around the catheter. Contouring of urethra started at bladder base and inferiorly extended to genitourinary diaphragm (always at least 0.5 cm caudally from the last slice of contoured apex of the prostate). The constraints for urethra recommended as ideal parameters relative to the prescribed doses were: urethra max D90 ! 110%, urethra max D1!130%. Urinary bladder volume was defined by the outer surface of the bladder wall. Bladder contour encompassed bladder neck and extended minimally 2 cm above the prostate base. Contouring and treatment were performed with partially filled urinary bladder using 150 mL of 0.9% NaCl solution. The recommended constraint was to keep the maximal dose received by the most exposed 2ccm of urinary bladder bellow 10.5 Gy. Treatment was delivered with the Varian Gamamed plus stepping source device using 192Ir with the activity of 0.7e1.4 Ci. EBRT, that typically preceded HDRB, was delivered as three-dimensional conformal radiation. Clinical target volume included prostate, distal 1/3e2/3 of seminal vesicles with lymph nodes along external, internal, and common iliac vessels if the risk of positive lymph nodes exceeded 15% according to the equation of Roach et al. (16). Prescribed dose was 50e50.4 Gy in 25e28 fractions. Study instrument for assessment of problems with UI To detect late effects of treatment and to allow to grade LUT according to various grading systems (17e19), an inhouse made questionnaire, used already for several years,
B. Kragelj, L. Zaletel-Kragelj / Brachytherapy
was used as the study instrument. Filling in this questionnaire is a part of standard procedure in prostate cancer patients at IOL, with main intention to register and grade side effects of the treatment. Questionnaire is filled in for the first time before the start of treatment, then after 6 and 12 months, and yearly thereafter. LUT was addressed regarding dysuria, frequency, hematuria, UI, and obstruction. Questions about UI were taken basically from the questionnaire presented by Skala et al. (20) with an additional question concerning number of pads used per day (Table 1). How distressing were problems with urinary function for patients was evaluated with 5-level scale (1 5 without problems to 5 5 big problems). Observed outcome The observed outcome was deterioration of UI (DUI) during the followup period longer than 1 year (the median followup period was 44.9 months). DUI was defined as the change in the grade of UI immediately before EBRT þ HDRB and the grade of UI in the second, the third, the fourth, and the fifth year of followup. The following scale was used: 1, major improvement (decrease in UI for two or more grades); 2, minor improvement (decrease in UI for one grade); 3, no change; 4, minor deterioration (increase in UI for one grade); and 5, major deterioration (increase in UI for two or more grades). Because minor and major deterioration were the categories of interest, these two categories were combined in the observed outcomedDUI (0 5 no and 1 5 yes). The UI grade was defined according to the following scale: 1, occasional urine dripping; 2, regular (about daily) urine dripping/intermittent use of incontinence pads; 3, persistent use of #2 incontinence pads; and 4, persistent use of O2 incontinence pads per day, basically representing SOMA scale (18) and Storey modification of RTOGe LENT delayed radiation toxicity grading (21). To achieve a sufficiently large number of observed persons, analysis of association between observed outcome and potential risk factors was carried out only in patients who completed 3 years of followup. The presence of DUI in the third year of followup was considered. Risk factors for DUI Two groups of risk factors were observed. The first group consisted of HDRB and supportive treatment factors:
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number of implanted needles (Nimplanted needles), planning imaging (1 5 CT and 2 5 MRI), number of interventions (Ninterventions) (0 5 1 and 1 5 O1) and dosimetric factors: PTV1, minimal dose received by 100% of the PTV1 (D100PTV1 ), minimal dose received by 90% of the PTV1 (D90 PTV1 ), minimal dose received by 100% of the PTV2 (D90 PTV2 ), urethral volume (Vurethra), mean urethral dose (D-MEANurethra), maximal dose received by 90% of the urethra volume (D90 urethra volume ), minimal dose received by 10% of the urethra volume (D10 urethra volume ), maximal dose received by 1% of the urethra volume (D1 urethra volume ), and maximal dose received by the most exposed 2 ccm of urinary bladder (D2ccbladder volume ). All dosimetric factors were retrospectively extracted from dose-volume histograms stored in electronic patients’ files. For the analysis, dose parameters for urinary bladder and urethra were converted to 2-Gy equivalent (EQD2) regarding the linear-quadratic model according to the standard equation: EQD2 5 D (d þ a/b)/(2 þ a/b), with a/b 5 3 Gy. As supportive treatment factor, the duration of androgen deprivation therapy (0 5 !12 months and 1 5 $12 months) was included. The second group consisted of patients’ characteristics extracted from patients’ files: age, comorbidity (hypertension, diabetes, coronary insufficiency, hyperlipidemia, history of cerebrovascular insult/peripheral deep venous thrombosis), anticoagulant treatment, initial UI (all 0 5 no and 1 5 yes), and initial nocturnal urination frequency (0 5 !3 urinations and 1 5 $3 urinations). Statistical analysis The univariate and multivariate analysis between DUI and potential risk factors was carried out. In both, univariate and multivariate analysis binary logistic regression (LR) was used. All variables that were meaningful for the observed outcome and univariately at least marginally statistically significantly associated with UI ( p ! 0.100) were included in the multivariate model (22). On the basis of LR model, the risk-score (logit) for each participant was calculated using the LR equation and afterward converted to the risk estimates for the observed outcome (22). Finally, the risk estimate values were put in an ordered series. At every value, the cut point was placed, a decision matrix defined taking into account the actual status of presence/absence of observed outcome, and nosological as well diagnostic test validity measures calculated (23e25). In addition, the receiver operating characteristic analysis was performed
Table 1 Questions addressing urinary incontinence problems in Ljubljana Institute of Oncology questionnaire about adverse health effects of radiation therapy Question
Predefined answers
Have you had problem with dripping or leaking urine? When you drip urine, about how much usually comes out? How often do you drip or leak urine? Do you wear pads or adult diapers? If you use pads, how often do you wear them? If you use pads daily, how many pads do you usually use per day?
Yes/no A few drops, less than a tablespoon, more than a tablespoon More than once a day, about once a day, less than once a day Yes/no Sometimes, daily One, two, three or more
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Table 2 Characteristics of dosimetric parameters of high-dose-rate brachytherapy in Ljubljana Institute of Oncology study of late toxicity after high-doserate brachytherapy boost treatment for prostate cancer
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(26). Decision about the best possible cut point was supported by calculating Youden index (26). On the basis of the LR equation at the end, the estimates of safe D2ccbladder volume for UI for patients with different characteristics considered in the LR model were calculated. In all statistical tests, p-value #0.05 was considered significant. SPSS version 21.0 was used for analysis.
4e60 ng/mL); Stage: T1 18/88 (20.5%), T2 40/88 (45.5%), and T3 30/88 (34.0%); and risk category: low 13/88 (14.8%), intermediate 27/88 (30.7%), and high 48/ 88 (54.5%). Androgen deprivation treatment was received by 81/88 (92.0%) patients (median duration 24 months [1e60 months]; duration less than 12 months: 10/81 (12.3%) patients). The most frequent comorbidity was hypertension (46/86, 53.5%), followed by hyperlipidemia (20/85, 23.5%), coronary insufficiency (17/86, 19.8%), history of cerebrovascular insult or peripheral deep venous thrombosis (11/86, 12.8%), and diabetes (10/85, 11.8%). During the EBRT þ HDRB, 22/86 (25.6%) of patients were receiving anticoagulation therapy. The most frequent micturition problems before treatment were obstructive problems found in 52/82 (63.4%) of patients followed by increased nocturnal micturition frequency in 32/87 (36.8%) and UI in 20/88 (22.7%) of patients. The prescribed dose to PTV1, 21 Gy, was delivered to 27/88 (30.7%) patients, whereas 18 Gy to 61/88 (69.3%) patients. Target volume was restricted to prostate in 79/88 (89.8%), whereas in 9/88 (10.2%) of patients, it was enlarged to enclose infiltrated parts of seminal vesicles. Dosimetric parameters of HDRB applied in the study are summarized in Table 2. Mean number of implanted needles was 15 3, whereas Ninterventions was one in 80/88 (90.9%) and two in 8/88 (9.1%) patients. CT-based planning was used in 30/88 (34.1%), whereas MRI was used in 58/88 (65.9%) patients.
Ethical considerations
Analysis of UI at the beginning of the study
Study protocol was approved by the Protocol and Ethical Committee of the Ljubljana Institute of Oncology.
At the start of treatment, UI was declared in 20/87 (22.9%) patients who had complete entry data: assessed as Grade 1 in 13/20 (65.0%), Grade 2 in 6/20 (30.0%), and as Grade 3 in 1/20 (5.0%) patients.
Dosimetric parameter
Minimum
Maximum
Mean SD
PTV1 D100PTV1 D90PTV1 D100PTV2 Vurethra D-MEANurethra (EQD2) D90urethra volume ðEQD2Þ D10urethra volume ðEQD2Þ D1urethra volume ðEQD2Þ D2ccbladder volume ðEQD2Þ
18 mL 8.3 Gy 13.4 Gy 12.8 Gy 1.2 mL 14.4 Gy 7.5 Gy 17.8 Gy 17.3 Gy 3.02 Gy
95 mL 17.1 Gy 24.6 Gy 23.7 Gy 4.0 mL 26.1 Gy 18.9 Gy 31.1 Gy 36.0 Gy 37.7 Gy
37.6 11.8 19.2 17.3 1.9 19.0 13.2 23.1 24.5 14.5
14.8 mL 1.9 Gy 2.0 Gy 2.1 Gy 0.8 mL 2.6 Gy 2.9 Gy 2.7 Gy 3.4 Gy 5.9 Gy
SD 5 standard deviation; PTV1 5 planning target volume 1; D100PTV1 5 minimal dose received by 100% of the PTV1; D90PTV1 5 minimal dose received by 90% of the PTV1; D100PTV2 5 minimal dose received by 100% of the PTV2; Vurethra 5 urethral volume; D-MEANurethra 5 mean urethral dose; D90urethra volume 5 minimal dose received by 90% of the urethra volume; D10urethra volume 5 minimal dose received by 10% of the urethra volume; D1urethra volume 5 minimal dose received by 1% of the urethra volume; D2ccbladder volume 5 maximal dose received by the most exposed 2ccm of urinary bladder; EQD2 5 2-Gy equivalent dose.
Results Analysis of DUI during the followup period
Description of the study group and treatment characteristics Patients in the study group were aged 67.6 6.1 years, with following tumor characteristics: Gleason score: #6 22/88 (25.0%), 7 37/88 (42.0%), and $8 29/88 (33.0%); percent of positive cores: median 50 (range 10e100); prostate-specific antigen: median 10 ng/mL (range,
The course of DUI after treatment in relation to initial problems is presented as a prevalence rates during the second, the third, the fourth, and the fifth year of observation (Table 3). In this time frame, it seems that with longer followup proportion of patients with DUI is increasing (Table 3).
Table 3 Prevalence rates of alteration of urinary incontinence in Ljubljana Institute of Oncology study of late toxicity after high-dose-rate brachytherapy boost treatment for prostate cancer Year of followup
N
Major improvement (%)
Minor improvement (%)
No change (%)
Minor deterioration (%)
Major deterioration (%)
2nd year 3rd year 4th year 5th year
84 81 47 30
0 0 0 0
6 5 1 1
62 59 32 19
11 10 8 5
5 7 6 5
(0) (0) (0) (0)
(7.1) (6.2) (2.1) (3.3)
(73.8) (72.8) (68.1) (63.3)
(13.1) (12.3) (17.0) (16.7)
(6.8) (8.6) (12.8) (16.7)
B. Kragelj, L. Zaletel-Kragelj / Brachytherapy
Analysis of association between DUI and potential risk factors Analysis was carried out in 81 patients who completed 3 years of followup. In 17 of them (20.9%), DUI was evidenced. In the group of HDRB and supportive treatment factors CT-based imaging, higher D100PTV2 ; D-MEANurethra, and D2ccbladder volume were statistically significantly associated with higher rates of DUI (Table 4). In the group of patients’ characteristics, the vast majority of factors did not show statistically significant association with DUI, the only exception was diabetes (Table 5). All data necessary to perform multivariate analysis were present in 76/81 patients (93.8%). The results showed that among the HDRB and supportive treatment factors, only D2ccbladder volume remained statistically significantly associated with observed outcome. For each Gy (EQD2) received by the most exposed 2ccm of urinary bladder, the odds for DUI increased for about 14%. Among the patients’ characteristics, diabetes in multivariate analysis not merely retained its predictive value, but its value even increased (the odds for DUI were about 6.7 times higher for diabetic patients). In addition, increased initial nocturnal micturition frequency defined with three or more micturitions per night, that was marginally significant in univariate analysis, became statistically significant in multivariate analysis.
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The odds for DUI and therefore for additional deterioration of already at the start of EBRT þ HDRB existing urinary problems are about 3.7 times higher than in the rest of patients. All other results are presented in Table 6. Finally, for each patient, the risk of DUI was estimated on the basis of the LR equation (logit 5 4.268 þ 1.906 diabetes þ 1.313 initial nocturnal micturition frequency $3 þ 0.133 D2ccurinary bladder volume ). The values varied between 0.0331 and 0.8870, with the median value 0.1310. The value of area under receiver operating characteristic curve was 0.790, indicating fair predictive performance of the model. The best cut point was placed at value 0.20656 (true-positive rate: 13/16 or 0.813; false-positive rate: 16/60 or 0.267; true-negative rate: 44/60 or 0.733; false-negative rate: 3/ 16 or 0.188; positive predictive value: 13/29 or 0.448; negative predictive value: 44/47 or 0.936; and Youden index: 0.546). The estimates of the safe D2ccbladder volume for UI for patients with different characteristics considered in the LR model are presented in Table 7.
Discussion Results of the study indicate that on long term the occurrence, or in the case of already existing UI, further DUI is related not only to treatment itself and to treatment-related
Table 4 Results of univariate logistic regression analysis of association between deterioration of urinary incontinence and treatment factors in Ljubljana Institute of Oncology study of late toxicity after high-dose-rate brachytherapy boost treatment for prostate cancer 95% CI limits for OR Risk factor
Ntot
Nimplanted needles Planning imaging CT MRI Ninterventions 1 O1 PTV1 (mL) D100PTV1 (Gy) D90PTV1 (Gy) D100PTV2 (Gy) Vurethra (mL) D-MEANurethra (EQD2) (Gy) D90urethra volume ðEQD2Þ (Gy) D10urethra volume ðEQD2Þ (Gy) D1urethra volume ðEQD2Þ (Gy) D2ccbladder volume ðEQD2Þ (Gy) Duration of androgen deprivation !12 months $12 months
81 81
81
Ndet/Ncat (%)
OR
Lower
Upper
p
0.96
0.79
1.18
0.709
10/28 (35.7) 7/53 (13.2)
1.00 0.27
0.09
0.83
0.022
16/73 (21.9) 1/8 (12.5)
1.00 0.51 0.99 1.08 1.07 1.13 0.64 1.08 1.04 1.03 1.03 1.27
0.06 0.96 0.94 0.98 1.03 0.30 1.02 0.97 0.99 0.99 1.03
4.45 1.04 1.22 1.17 1.24 1.35 1.15 1.13 1.08 1.06 1.23
0.541 0.864 0.279 0.152 0.011 0.240 0.014 0.278 0.149 0.109 0.009
2/9 (22.2) 11/60 (18.3)
1.00 0.79
0.14
4.31
0.781
80 81 81 80 80 80 81 80 81 79 69
Ntot 5 total number of observations; Ndet 5 number of patients with deterioration; Ncat 5 number of patients within the category; OR 5 odds ratio; CI 5 confidence interval; PTV1 5 planning target volume 1; D100PTV1 5 minimal dose received by 100% of the PTV1; D90PTV1 5 minimal dose received by 90% of the PTV1; D100PTV2 5 minimal dose received by 100% of the PTV2; Vurethra 5 urethral volume; D-MEANurethra 5 mean urethral dose; D90urethra volume 5 minimal dose received by 90% of the urethra volume; D10urethra volume 5 minimal dose received by 10% of the urethra volume; D1urethra volume 5 minimal dose received by 1% of the urethra volume; D2ccbladder volume 5 maximal dose received by the most exposed 2ccm of urinary bladder; EQD2 5 2-Gy equivalent dose.
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Table 5 Results of univariate logistic regression analysis of association between deterioration of urinary incontinence and patients’ characteristics in Ljubljana Institute of Oncology study of late toxicity after high-dose-rate brachytherapy boost treatment for prostate cancer 95% CI limits for OR Risk factor Ntot Ndet/Ncat (%) OR
Lower
Age 81 0.94 Hypertension No 79 6/36 (16.7) 1.00 Yes 10/43 (23.3) 1.52 Diabetes No 78 12/70 (17.1) 1.00 Yes 4/8 (50.0) 4.83 Hyperlipidemia No 78 12/61 (19.7) 1.00 Yes 3/17 (17.6) 0.88 CVI No 79 16/69 (23.2) NA Yes 0/10 (0.0) NA Coronary insufficiency No 79 13/63 (20.6) 1.00 Yes 3/16 (18.8) 0.899 Anticoagulation treatment No 79 14/59 (23.7) 1.00 Yes 2/20 (10.0) 0.357 Initial nocturnal micturition frequency !3 81 8/53 (15.1) 1.00 $3 9/28 (32.1) 2.67 Initial urinary incontinence No 81 12/63 (19.0) 1.00 Yes 5/18 (27.8) 1.64 Initial urinary obstruction No 78 3/28 (10.7) 1.00 Yes 13/50 (26.5) 2.93
0.85
Upper 1.03
0.156
4.76
0.470
1.06
22.08
0.042
0.22
3.54
0.851
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Table 6 Results of multivariate logistic regression analysis of association between deterioration of urinary incontinence and selected treatment factors and patients’ characteristics in Ljubljana Institute of Oncology study of late toxicity after high-dose-rate brachytherapy boost treatment for prostate cancer (N 5 76) 95% CI limits for OR
p
0.49
/ /
-
/ /
0.22
3.58
0.867
0.07
1.73
0.201
0.89
7.95
0.079
0.49
5.47
0.425
0.76
11.34
0.120
Ntot 5 total number of observations; Ndet 5 number of patients with deterioration; Ncat 5 number of patients within the category; OR 5 odds ratio; CI 5 confidence interval; NA 5 not applicable; CVI 5 history of cerebrovascular insult/peripheral deep venous thrombosis.
parameters, but it seems that patients’ characteristics are equally important and predictive. The dose received by the bladder base was more or less neglected in studies that tried to relate dosimetric factors of HDRB and LUT (3, 6, 9, 13, 14) and was mostly unused as a normal-dose constraint in the planning process (3,9,13,14,27e29). Two recent studies, the Hathout study of LDRPB (30) and the Mazeron study of advanced cervical cancer treatment with pulsed dose rate uterovaginal brachytherapy and EBRT (31), stressed the link between LUT and dose received by the bladder base. In the Hathout study (30), the minimal dose received by 2ccm of the bladder neck was found to be the strongest predictor for acute and LUT defined by I-PSS. Bladder neck dose was more important also in relation to D2ccbladder volume that loses its significance as independent predictor for LUT in multivariate analysis. It is unclear whether these findings could be considered for EBRT þ HDRB and UI as the observed outcome. However, UI was the observed outcome in the
Risk factor
b
OR
Diabetes No 1.00 Yes 1.906 6.73 Initial nocturnal micturition frequency !3 1.00 $3 1.313 3.72 D2ccbladder volume ðEQD2Þ (Gy) 0.133 1.14 Constant 4.268
Lower
Upper
p
0.96 1.17
1.57 38.56
0.032
1.03 1.03
13.04 1.26
0.045 0.010
OR 5 odds ratio; CI 5 confidence interval; D2ccbladder volume 5 maximal dose received by the most exposed 2ccm of urinary bladder; EQD2 5 2Gy equivalent dose.
Mazeron study (31): for the group of patients with D2ccbladder volume close to bladder neck, a significant correlation between the D2ccbladder volume and incontinence that necessitate pads was reported. Together with stated importance of dose to the bladder base a common point with our findings is also a quite similar proposed threshold sum EQD2 dose of EBRT and D2ccbladder volume dose $75 Gy. According to American Brachytherapy Society guidelines, significant urinary symptoms are a relative contraindication to EBRT þ HDRB, but patients should possibly expect worsening of urinary function (27). Our study confirmed that statement. The correlation between baseline urinary symptoms and LUT was evidenced for LDRPB (32e34) and EBRT (35). However, urinary problems at the beginning of the treatment not merely correlated to LUT but actually increased the risk of further deterioration of urinary problems. This phenomenon seems to be first reported in our study. Comorbidities except transurethral resection were not regularly emphasized in the studies of LUT after EBRT þ HDRB. According to our study, diabetes seems to be more important predictor for UI than dosimetric Table 7 The estimates of the safe doses for the most exposed 2ccm of urinary bladder (D2ccbladder volume ðEQD2Þ ) for deterioration of urinary incontinence (DUI) for patients with different characteristics considered in the logistic regression model Initial nocturnal Combination of micturition Estimate characteristics Diabetes frequency of the safe D2ccbladder volume ðEQD2Þ dose 1 2 3 4
No No Yes Yes
!3 $3 !3 $3
EQD2 5 2-Gy equivalent dose.
21.9 Gy 12.0 Gy 7.6 Gy No safe dose for DUI
B. Kragelj, L. Zaletel-Kragelj / Brachytherapy
parameters and other patients’ characteristics. Diabetes by itself was found as a strong predictor for UI (36, 37) and was identified as a predictor of LUT concerning frequency and dysuria after EBRT for prostate cancer (38, 39). There are no data about the predictive role of diabetes for late UI after EBRT þ HDRB. According to our experience, comorbidity including diabetes is important predictor for LUT. Limitations of the study First, one could argue that instead of internationally validated questionnaire, an IOL in-house made questionnaire was used as a study instrument. However, at IOL, this instrument was used already for several years and replacing the questionnaire would affect the comparability of responses in time. Second, in our study, UI was not quantified in the sense of scoring, as it is possible by validated healthrelated quality-of-life instruments. Instead of that, UI was classified into standard toxicity grades, and as a measure of deterioration, only a two-stage system was used. With this simplified system, a rather robust assessment of UI deterioration was achieved. Statistically significant correlation between DUI and patient-reported micturition quality confirmed its validity. However, small, but for quality-oflife perhaps important changes, may be missed. Yet with the use of self-administered questionnaires that take into account different expressions of UI a reliable, and patient-oriented information was gathered. Finally, a relation to DUI was searched only in dose-volume parameters of brachytherapy treatment, and the impact of dose-volume histogram parameters of EBRT was neglected. That also EBRT component of combined treatment has perhaps important effect on LUT is suggested from studies comparing different combinations of radiation treatment (5,40). However, the aim of the study was to optimize brachytherapy part of the treatment, some for brachytherapy important data may be obscured by adding EBRT data, and for that reason, EBRT data were omitted. The importance of the study results for clinical practice Study discloses parameters involved in the development of DUI. Taking account of diabetes and nocturia as risk factors, three dose constraints for the total EQD2 as the sum of HDRB urinary D2ccbladder volume and mean EBRT prostate EQD2 can be suggested: 72 Gy for patients without risk factors, with additional diabetes 57 Gy, and for patients with high initial nocturnal micturition frequency 62 Gy. It seems that in patients with both risk factors, it is impossible to retain this low risk of DUI (!6%) and to them perhaps other forms of prostate cancer treatment should be offered. Here, we can stress the strengths of the study. First, the concept of dealing with dose restrictions in connection with patients’ characteristics is not a common practice in radiotherapy. In our case, consideration of patient’s characteristics improves the predictive value of merely D2ccbladder volume :
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The estimates of safe doses for D2ccbladder volume are therefore given in conjunction with information on diabetes status and nocturnal micturition frequency. Suggested restraints are indicated with fair predictive performance of the model and high negative predictive value, which allows HDRB with low risk of UI. Second, the urinary bladder base is not universally accepted as an organ at risk in HDRB (30). The identified relationship between UI and urinary bladder base dose suggests that the latter should be considered in the planning procedure. Contouring of the lowest 1.5 cm of urinary bladder seems to be sufficient to get reliable information about the dose to its most exposed part. Possibilities for further research in the field It is unclear whether detrusor overactivity involved in the emergence of UI early after LDRPB (41) could be the cause for late UI after LDRPB and EBRT þ HDRB. Urodynamic studies are needed to elucidate pathophysiology of UI (42) and also to better disclose patients at increased risk for UI. The predictive role of urinary D2ccbladder volume for UI suggests that bladder base contains structures crucial for the emergence of UI. Bladder neck and trigone area were implicated as critical structures for LDRPB and cervical cancer brachytherapy. However, critical structure for UI after EBRT þ HDRB is still needed to be identified.
Conclusion The present study discloses the impact of characteristics of patients as well as particular structures and dosimetric parameters in the emergence of LUT. Diabetes, nocturnal micturitions, and the D2ccbladder volume are identified as independent predictors for DUI. Taking account of these parameters a set of dose constraints is suggested to reduce the DUI. However, additional studies are needed not only to validate suggested dose constraints but also to improve understanding of underlying pathophysiology and to more precisely identify structures involved in the process of late UI. References [1] Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate cancer survivors. N Engl J Med 2008;358:1250e1256. [2] Vargas CE, Martinez AA, Boike TP, et al. High-dose irradiation for prostate cancer via high-dose-rate brachytherapy boost: results of a phase I to II study. Int J Radiat Oncol Biol Phys 2006;66:416e423. [3] Ghadjar P, Rentsch CA, Isaak B, et al. Urethral toxicity vs. cancer control- lessons to be learned from high-dose rate brachytherapy combined with intensity-modulated radiation therapy in intermediateand high-risk prostate cancer. Brachytherapy 2011;10:286e294. [4] Martınez-Monge R, Moreno M, Ciervide R, et al. External-beam radiation therapy and high-dose rate brachytherapy combined with long-term androgen deprivation therapy in high and very high prostate cancer: preliminary data on clinical outcome. Int J Radiat Oncol Biol Phys 2012;82:469e476.
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[5] Mohammed N, Kestin L, Ghilezan M, et al. Comparison of acute and late toxicities for three modern high-dose radiation treatment techniques for localized prostate cancer. Int J Radiat Oncol Biol Phys 2012;82:204e212. [6] Hsu IC, Hunt D, Straube W, et al. Dosimetric analysis of radiation therapy oncology group 0321: the importance of urethral dose. Pract Radiat Oncol 2014;4:27e34. [7] Smith DP, King MT, Egger S, et al. Quality of life three years after diagnosis of localised prostate cancer: population based cohort study. BMJ 2009;339:b4817. [8] Pinkawa M, Fischedick K, Treusacher P, et al. Dose-volume impact in high-dose-rate Iridium-192 brachytherapy as a boost to external beam radiotherapy for localized prostate cancer-a phase I study. Radiother Oncol 2006;78:41e46. [9] Duchesne GM, Das R, Toye W. Dose distribution and morbidity after high dose rate brachytherapy for prostate cancer: influence of V150 and V200 parameters. Australas Radiol 2002;46:384e389. [10] Galalae RM, Kovacs G, Schultze J, et al. Long-term outcome after elective irradiation of the pelvic lymphatics and local dose escalation using high-dose-rate brachytherapy for locally advanced prostate cancer. Int J Radiat Oncol Biol Phys 2002;52:81e90. [11] Astr€ om L, Pedersen D, Mercke C, et al. Long-term outcome of high dose rate brachytherapy in radiotherapy of localised prostate cancer. Radiother Oncol 2005;74:157e161. [12] Luo HL, Fang FM, Kang CH, et al. Can high-dose-rate brachytherapy prevent the major genitourinary complication better than external beam radiation alone for patients with previous transurethral resection of prostate. Int Urol Nephrol 2013;45:113e119. [13] Hashimoto Y, Akimoto T, Iizuka J, et al. Correlation between the changes in the EPIC QOL scores and the dose-volume histogram parameters in high-dose-rate brachytherapy combined with hypofractionated external beam radiation therapy for prostate cancer. Jpn J Clin Oncol 2015;45:81e87. [14] Ishiyama H, Kitano M, Satoh T, et al. Genitourinary toxicity after high-dose-rate (HDR) brachytherapy combined with hypofractionated external beam radiotherapy for localized prostate cancer: an analysis to determine the correlation between dose-volume histogram parameters in HDR brachytherapy and severity of toxicity. Int J Radiat Oncol Biol Phys 2009;75:23e28. [15] D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969e974. [16] Roach M 3rd, Marquez C, Yuo HS, et al. Predicting the risk of lymph node involvement using the pre-treatment prostate specific antigen and Gleason score in men with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1994;28:33e37. [17] Cox JD, Stetz JA, Pajak TF. Toxicity criteria of the radiation therapy oncology group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341e1346. [18] Marks LB, Carroll PR, Dugan TC, Anscher MS. The response of the urinary bladder, urethra, and ureter to radiation and chemotherapy. Int J Radiat Oncol Biol Phys 1995;31:1257e1280. [19] Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS;. Publish Date: August 9, 2006. Available at: http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed December 12, 2015. [20] Skala M, Rosewall T, Dawson L, et al. Patient-assessed late toxicity rates and principal component analysis after image-guided radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys 2007;68:690e698. [21] Storey MR, Pollack A, Zagars G, et al. Complications from radiotherapy dose escalation in prostate cancer: preliminary report of a randomized trial. Int J Radiat Oncol Biol Phys 2000;48:635e642. [22] Hosmer DW, Lemeshow S. Applied logistic regression. New York (NY): John Wiley&Sons; 2000.
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[23] McNeil BJ, Keeler E, Adelstein JS. Primer on certain elements of medical decision making. N Engl J Med 1975;293:211e215. [24] Bradley GW, editor. Disease, diagnosis and decisions. Chichester: John Wiley&Sons; 1993. [25] Kallin Westin L. Receiver operating characteristic (ROC) analysis: valuating discriminance effects among decision support systems. Umea: Umea University, Department of Computing Science; 2001. [26] Schisterman EF, Perkins NJ, Liu A, Bondell H. Optimal cut-point and corresponding Youden index to discriminate individuals using pooled blood samples. Epidemiology 2005;16:73e81. [27] Yamada Y, Rogers L, Demanes DJ, et al. American brachytherapy society consensus guidelines for high-dose-rate prostate brachytherapy. Brachytherapy 2012;11:20e32. [28] Hoskin PJ, Colombo A, Henry A, et al. GEC/ESTRO recommendations on high dose rate afterloading brachytherapy for localised prostate cancer: an update. Radiother Oncol 2013;107:325e332. [29] Zwahlen DR, Andrianopoulos N, Matheson B, et al. High-dose-rate brachytherapy in combination with conformal external beam radiotherapy in the treatment of prostate cancer. Brachytherapy 2010;9:27e35. [30] Hathout L, Folkert MR, Kollmeier MA, et al. Dose to the bladder neck is the most important predictor for acute and late toxicity after low-dose-rate prostate brachytherapy: indications for establishing new dose constraints for treatment planning. Int J Radiat Oncol Biol Phys 2014;90:312e319. [31] Mazeron R, Dumas I, Rivin E, et al. D2cm3/DICRU ratio as a surrogate of bladder hotspots localizations during image-guided adaptive brachytherapy for cervical cancer: assessment and implications in late urinary morbidity analysis. Brachytherapy 2015;14:300e307. [32] Steggerda MJ, Witteveen T, van den Boom F, Moonen LM. Is there a relation between the radiation dose to the different sub-segments of the lower urinary tract and urinary morbidity after brachytherapy of the prostate with J-125 seeds. Radiother Oncol 2013;109:251e255. [33] Malick S, Azzouzi R, Cormier L, et al. Urinary morbidity after 125I brachytherapy of the prostate. BJU Int 2003;92:555e558. [34] Wehle MJ, Lisson SW, Buskirk SJ, et al. Prediction of genitourinary tract morbidity after brachytherapy for prostate adenocarcinoma. Mayo Clin Proc 2004;79:314e317. [35] Barnett GC, De Meerleer G, Gulliford SL, et al. The impact of clinical factors on the development of late radiation toxicity: results from the Medical Research Council RT01 Trial (ISRCTN 47772397). Clin Oncol 2011;23:613e624. [36] Danforth KN, Townsend MK, Curhan GC, et al. Type 2 diabetes mellitus and risk of stress, urge and mixed urinary incontinence. J Urol 2009;181:193e197. [37] Brown JS, Vittinghoff E, Lin F, et al. Prevalence and risk factors for urinary incontinence in women with type 2 diabetes and impaired fasting glucose: findings from the National Health and Nutrition Examination Survey (NHANES) 2001e2002. Diabetes Care 2006;29: 1307. [38] Mathieu R, Arango JDO, Beckendorf V, et al. Nomograms to predict late urinary toxicity after prostate cancer radiotherapy. World J Urol 2014;32:743e751. [39] Yahya N, Ebert MA, Bulsara M, et al. Dosimetry, clinical factors and medication intake influencing urinary symptoms after prostate radiotherapy: an analysis of data from the RADAR prostate radiotherapy trial. Radiother Oncol 2015;116:112e118. [40] Lawton CA, Yan Y, Lee WR, et al. Long-term results of an RTOG phase II trial (00-19) of external-beam radiation therapy combined with permanent source brachytherapy for intermediate-risk clinically localized adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 2012;82:e795ee801. 41 Blaivas JG, Weiss JP, Jones M. The pathophysiology of lower urinary tract symptoms after brachytherapy for prostate cancer. BJU Int 2006; 98:1233e1237. 42 Rosier PF, Giarenis I, Valentini FA, et al. Do patients with symptoms and signs of lower urinary tract dysfunction need a urodynamic diagnosis? ICI-RS 2013. Neurourol Urodyn 2014;33:581e586.
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Urinary incontinence after high-dose-rate brachytherapy boost treatment for prostate cancer Borut Kragelj1,*, Lijana Zaletel-Kragelj2 2
1 Department of Brachytherapy, Institute of Oncology Ljubljana, Ljubljana, Slovenia Department of Public Health, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
ABSTRACT
PURPOSE: To evaluate urinary incontinence (UI) and to elucidate potential risk factors important for the appearance or deterioration of pre-existing UI after high-dose-rate boost treatment of prostate cancer. METHODS AND MATERIALS: The change in grade of UI regarding the state at the start of treatment was assessed in 88 patients, consecutively treated from October 2006 through April 2011 with high-dose-rate brachytherapy of 3 6e7 Gy to 50e50.4 Gy of external-beam radiation. Increase in UI grade was defined as deterioration of UI (DUI). The impact of patients and treatment characteristics on third year prevalence of DUI was analyzed by using binary logistic regression method. RESULTS: At third year, DUI of followup was evidenced in 17/81 (20.9%) patients. It significantly impacted micturition quality ( p 5 0.015) and was associated with D2ccbladder volume (odds ratio [OR]: 1.14; 95% confidence interval [CI]: 1.03e1.26; p 5 0.010), diabetes (OR: 6.73; 95% CI: 1.17e38.56; p 5 0.032), and initial nocturnal micturition frequency (OR: 3.72; 95% CI: 1.03e 13.04; p 5 0.045). Based on a multivariate model, a range of ‘‘safe’’ D2ccbladder volume ðEQD2Þ doses is suggested (no risk factor: 21.9 Gy, frequent initial nocturnal micturition only: 12.0 Gy, diabetes only: 7.6 Gy, both risk factors: no safe dose). CONCLUSIONS: The study featured on urinary bladder base as a risk structure for UI. By taking account of the dose to urinary bladder base in conjunction with diabetes and initial nocturnal micturition frequency, the risk of UI could be reduced. Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Urinary incontinence; High-dose-rate brachytherapy; Prostate cancer
Introduction Urinary incontinence (UI) is one of the adverse effects that may occur after various forms of radical local prostate cancer treatment. It may be a lifelong complication with significant impact on patients’ outcome satisfaction (1). UI can be expected also after the external-beam radiation (EBRT) and high-dose-rate brachytherapy (HDRB) boost treatment (2e9). The reported rates of UI after EBRT þ HDRB are highly variable, and several factors may be implicated for this dispersity of data such as different definitions or different methods of assessment.
Received 9 February 2016; received in revised form 22 March 2016; accepted 23 March 2016. * Corresponding author. Institute of Oncology, Zaloska 2, Ljubljana, Slovenia. Tel.: þ386-1-5879-489; fax: þ386-1-5879-400. E-mail address: [email protected] (B. Kragelj).
In institutional series, the reported incidence of UI is up to 22% (3) with up to 4% rate of UI required the use of pads (4). Higher rates of more pronounced form of UI were reported if quality-of-life questionnaires were used to obtain data (7, 8). In terms of UI, EBRT þ HDRB is comparable to other modes of radiation treatmentdsole EBRT and low-doserate brachytherapy (LDRPB) (5, 7) When compared to radical prostatectomy, EBRT þ HDRB is as advantageous as other forms of radiation treatment (7). However, reported followup of patients after EBRT þ HDRB is short and UI after EBRT þ HDRB, unlike other treatments, seemed to increase with longer observation (7). Clinical and dosimetric parameters as well as critical organs implicated in UI after EBRT þ HDRB are largely unknown. Nevertheless, there exist some studies that provide valuable information. For example, Galalae et al. (10) have identified the relationship between the interval of less than
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6 months to transurethral resection with a significant increase of UI. However, in general, the rate of UI was very low. Astr€ om et al. (11) and Luo et al. (12) showed basically identical very favorable outcomes of HDR brachytherapy for prostate cancer associated with very low rates of UI and significantly lower vs. EBRT alone. In consequence, the results of these three studies were perfectly in line demonstrating superiority of prostate HDR brachytherapy in terms of radiotherapy-related toxicity in comparison with alternative boost methods. More is known about late-urinary toxicity (LUT) on general. Several dosimetric studies pointed at prostatic urethra as a critical organ (6, 8, 13, 14). LUT is related to either volumes of urethra that received doses higher than the prescribed dose (6, 14) or to high doses received by the small fragments of urethra (8, 13). Similar relation between LUT and the regions that received high doses was shown also for the whole prostate (3, 6, 9, 13). Critical are doses 10e100% higher than the prescribed dose with related volumes. However, generalization of these predictive factors for LUT on UI seems not to be absolutely reliable as at least in some of the aforementioned studies UI represented only a small part of LUT. Aiming at individualizing treatment and improving safety of EBRT þ HDRB, the objective of the study was to define patients’ and treatment’s characteristics that are related specifically to UI. Methods and materials Patients In the followup study, 88 patients, consecutively treated by the author with EBRT þ HDRB at the Institute of Oncology Ljubljana (IOL) in the period 2006e2011, were included. EBRT þ HDRB was primarily offered to patients with intermediate- or high-risk clinically localized or locally advanced prostate cancer (15) and to low-risk patients who refused to get radical prostatectomy, if feasible for brachytherapy. In general, patients were considered eligible for EBRT þ HDRB if ultrasound showed no pubic arch interference, were eligible to undergo regional anesthesia with spinal block, and eligible to perform CT/MRI scan. Treatment characteristics Brachytherapy was performed with the patient in lithotomy position and consisted of TRUS-guided transperineal insertion of 20- or 30-cm-long closed-end plastic needles into the prostate and in selected patients also into the initial part of seminal vesicles, the use of the in-house made template that allows also needle fixation and aerated xylocaine gel in the Foley catheter to improve visibility of urethra. Needles were typically placed into prostate periphery and suburethraly. Finally, cystoscopy was performed with patient in recumbent
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position with extended legs for determining the final position of the tips of needles beneath bladder mucosa. After completion of the implant procedure, CT (slice thickness 1.6 mm) or MRI scan (T2-weighted fast-spin echo paratransversal sequence and fast recovery 3D fast-spin echo sequence with 1 mm isotropic voxels) was acquired for planning purposes. Brachyvision planning system was used for image registration, contouring, and dosimetry. Two planning target volumes (PTVs) were routinely defined: PTV1 encircled the prostate with additional 3-mm margin around the zone of suspected capsular invasion, whereas PTV2 encircled peripheral part of the prostate. When visible on the MRI images, also gross tumor volume was defined and included in the PTV2. Initially, prescribed dose was 21 Gy to PTV1 and 22.5 Gy to PTV2, with 7 Gy and 7.5 Gy per fraction, respectively. Later, the dose was reduced to 18 Gy to PTV1 and 19.5 Gy to PTV2, also given in three fractions. The biologically equivalent doses for PTV1 and accepting an a/b 5 1.5 were 119 Gy and 90 Gy respectively. Implanted fiducial markers (1.2 3e5 mm sized gold seeds) and in most patients CT scan were used to estimate needle shift before the third fraction. Interfraction interval was 6e8 hours. However, in case of excessive overnight needle shift that could not be compensated with extraplanning, an additional implantation was performed for the delivery of the third treatment fraction. Urethra was identified with the urinary catheter. The contour enclosed also the additional 1- to 2-mm margin around the catheter. Contouring of urethra started at bladder base and inferiorly extended to genitourinary diaphragm (always at least 0.5 cm caudally from the last slice of contoured apex of the prostate). The constraints for urethra recommended as ideal parameters relative to the prescribed doses were: urethra max D90 ! 110%, urethra max D1!130%. Urinary bladder volume was defined by the outer surface of the bladder wall. Bladder contour encompassed bladder neck and extended minimally 2 cm above the prostate base. Contouring and treatment were performed with partially filled urinary bladder using 150 mL of 0.9% NaCl solution. The recommended constraint was to keep the maximal dose received by the most exposed 2ccm of urinary bladder bellow 10.5 Gy. Treatment was delivered with the Varian Gamamed plus stepping source device using 192Ir with the activity of 0.7e1.4 Ci. EBRT, that typically preceded HDRB, was delivered as three-dimensional conformal radiation. Clinical target volume included prostate, distal 1/3e2/3 of seminal vesicles with lymph nodes along external, internal, and common iliac vessels if the risk of positive lymph nodes exceeded 15% according to the equation of Roach et al. (16). Prescribed dose was 50e50.4 Gy in 25e28 fractions. Study instrument for assessment of problems with UI To detect late effects of treatment and to allow to grade LUT according to various grading systems (17e19), an inhouse made questionnaire, used already for several years,
B. Kragelj, L. Zaletel-Kragelj / Brachytherapy
was used as the study instrument. Filling in this questionnaire is a part of standard procedure in prostate cancer patients at IOL, with main intention to register and grade side effects of the treatment. Questionnaire is filled in for the first time before the start of treatment, then after 6 and 12 months, and yearly thereafter. LUT was addressed regarding dysuria, frequency, hematuria, UI, and obstruction. Questions about UI were taken basically from the questionnaire presented by Skala et al. (20) with an additional question concerning number of pads used per day (Table 1). How distressing were problems with urinary function for patients was evaluated with 5-level scale (1 5 without problems to 5 5 big problems). Observed outcome The observed outcome was deterioration of UI (DUI) during the followup period longer than 1 year (the median followup period was 44.9 months). DUI was defined as the change in the grade of UI immediately before EBRT þ HDRB and the grade of UI in the second, the third, the fourth, and the fifth year of followup. The following scale was used: 1, major improvement (decrease in UI for two or more grades); 2, minor improvement (decrease in UI for one grade); 3, no change; 4, minor deterioration (increase in UI for one grade); and 5, major deterioration (increase in UI for two or more grades). Because minor and major deterioration were the categories of interest, these two categories were combined in the observed outcomedDUI (0 5 no and 1 5 yes). The UI grade was defined according to the following scale: 1, occasional urine dripping; 2, regular (about daily) urine dripping/intermittent use of incontinence pads; 3, persistent use of #2 incontinence pads; and 4, persistent use of O2 incontinence pads per day, basically representing SOMA scale (18) and Storey modification of RTOGe LENT delayed radiation toxicity grading (21). To achieve a sufficiently large number of observed persons, analysis of association between observed outcome and potential risk factors was carried out only in patients who completed 3 years of followup. The presence of DUI in the third year of followup was considered. Risk factors for DUI Two groups of risk factors were observed. The first group consisted of HDRB and supportive treatment factors:
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number of implanted needles (Nimplanted needles), planning imaging (1 5 CT and 2 5 MRI), number of interventions (Ninterventions) (0 5 1 and 1 5 O1) and dosimetric factors: PTV1, minimal dose received by 100% of the PTV1 (D100PTV1 ), minimal dose received by 90% of the PTV1 (D90 PTV1 ), minimal dose received by 100% of the PTV2 (D90 PTV2 ), urethral volume (Vurethra), mean urethral dose (D-MEANurethra), maximal dose received by 90% of the urethra volume (D90 urethra volume ), minimal dose received by 10% of the urethra volume (D10 urethra volume ), maximal dose received by 1% of the urethra volume (D1 urethra volume ), and maximal dose received by the most exposed 2 ccm of urinary bladder (D2ccbladder volume ). All dosimetric factors were retrospectively extracted from dose-volume histograms stored in electronic patients’ files. For the analysis, dose parameters for urinary bladder and urethra were converted to 2-Gy equivalent (EQD2) regarding the linear-quadratic model according to the standard equation: EQD2 5 D (d þ a/b)/(2 þ a/b), with a/b 5 3 Gy. As supportive treatment factor, the duration of androgen deprivation therapy (0 5 !12 months and 1 5 $12 months) was included. The second group consisted of patients’ characteristics extracted from patients’ files: age, comorbidity (hypertension, diabetes, coronary insufficiency, hyperlipidemia, history of cerebrovascular insult/peripheral deep venous thrombosis), anticoagulant treatment, initial UI (all 0 5 no and 1 5 yes), and initial nocturnal urination frequency (0 5 !3 urinations and 1 5 $3 urinations). Statistical analysis The univariate and multivariate analysis between DUI and potential risk factors was carried out. In both, univariate and multivariate analysis binary logistic regression (LR) was used. All variables that were meaningful for the observed outcome and univariately at least marginally statistically significantly associated with UI ( p ! 0.100) were included in the multivariate model (22). On the basis of LR model, the risk-score (logit) for each participant was calculated using the LR equation and afterward converted to the risk estimates for the observed outcome (22). Finally, the risk estimate values were put in an ordered series. At every value, the cut point was placed, a decision matrix defined taking into account the actual status of presence/absence of observed outcome, and nosological as well diagnostic test validity measures calculated (23e25). In addition, the receiver operating characteristic analysis was performed
Table 1 Questions addressing urinary incontinence problems in Ljubljana Institute of Oncology questionnaire about adverse health effects of radiation therapy Question
Predefined answers
Have you had problem with dripping or leaking urine? When you drip urine, about how much usually comes out? How often do you drip or leak urine? Do you wear pads or adult diapers? If you use pads, how often do you wear them? If you use pads daily, how many pads do you usually use per day?
Yes/no A few drops, less than a tablespoon, more than a tablespoon More than once a day, about once a day, less than once a day Yes/no Sometimes, daily One, two, three or more
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Table 2 Characteristics of dosimetric parameters of high-dose-rate brachytherapy in Ljubljana Institute of Oncology study of late toxicity after high-doserate brachytherapy boost treatment for prostate cancer
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(26). Decision about the best possible cut point was supported by calculating Youden index (26). On the basis of the LR equation at the end, the estimates of safe D2ccbladder volume for UI for patients with different characteristics considered in the LR model were calculated. In all statistical tests, p-value #0.05 was considered significant. SPSS version 21.0 was used for analysis.
4e60 ng/mL); Stage: T1 18/88 (20.5%), T2 40/88 (45.5%), and T3 30/88 (34.0%); and risk category: low 13/88 (14.8%), intermediate 27/88 (30.7%), and high 48/ 88 (54.5%). Androgen deprivation treatment was received by 81/88 (92.0%) patients (median duration 24 months [1e60 months]; duration less than 12 months: 10/81 (12.3%) patients). The most frequent comorbidity was hypertension (46/86, 53.5%), followed by hyperlipidemia (20/85, 23.5%), coronary insufficiency (17/86, 19.8%), history of cerebrovascular insult or peripheral deep venous thrombosis (11/86, 12.8%), and diabetes (10/85, 11.8%). During the EBRT þ HDRB, 22/86 (25.6%) of patients were receiving anticoagulation therapy. The most frequent micturition problems before treatment were obstructive problems found in 52/82 (63.4%) of patients followed by increased nocturnal micturition frequency in 32/87 (36.8%) and UI in 20/88 (22.7%) of patients. The prescribed dose to PTV1, 21 Gy, was delivered to 27/88 (30.7%) patients, whereas 18 Gy to 61/88 (69.3%) patients. Target volume was restricted to prostate in 79/88 (89.8%), whereas in 9/88 (10.2%) of patients, it was enlarged to enclose infiltrated parts of seminal vesicles. Dosimetric parameters of HDRB applied in the study are summarized in Table 2. Mean number of implanted needles was 15 3, whereas Ninterventions was one in 80/88 (90.9%) and two in 8/88 (9.1%) patients. CT-based planning was used in 30/88 (34.1%), whereas MRI was used in 58/88 (65.9%) patients.
Ethical considerations
Analysis of UI at the beginning of the study
Study protocol was approved by the Protocol and Ethical Committee of the Ljubljana Institute of Oncology.
At the start of treatment, UI was declared in 20/87 (22.9%) patients who had complete entry data: assessed as Grade 1 in 13/20 (65.0%), Grade 2 in 6/20 (30.0%), and as Grade 3 in 1/20 (5.0%) patients.
Dosimetric parameter
Minimum
Maximum
Mean SD
PTV1 D100PTV1 D90PTV1 D100PTV2 Vurethra D-MEANurethra (EQD2) D90urethra volume ðEQD2Þ D10urethra volume ðEQD2Þ D1urethra volume ðEQD2Þ D2ccbladder volume ðEQD2Þ
18 mL 8.3 Gy 13.4 Gy 12.8 Gy 1.2 mL 14.4 Gy 7.5 Gy 17.8 Gy 17.3 Gy 3.02 Gy
95 mL 17.1 Gy 24.6 Gy 23.7 Gy 4.0 mL 26.1 Gy 18.9 Gy 31.1 Gy 36.0 Gy 37.7 Gy
37.6 11.8 19.2 17.3 1.9 19.0 13.2 23.1 24.5 14.5
14.8 mL 1.9 Gy 2.0 Gy 2.1 Gy 0.8 mL 2.6 Gy 2.9 Gy 2.7 Gy 3.4 Gy 5.9 Gy
SD 5 standard deviation; PTV1 5 planning target volume 1; D100PTV1 5 minimal dose received by 100% of the PTV1; D90PTV1 5 minimal dose received by 90% of the PTV1; D100PTV2 5 minimal dose received by 100% of the PTV2; Vurethra 5 urethral volume; D-MEANurethra 5 mean urethral dose; D90urethra volume 5 minimal dose received by 90% of the urethra volume; D10urethra volume 5 minimal dose received by 10% of the urethra volume; D1urethra volume 5 minimal dose received by 1% of the urethra volume; D2ccbladder volume 5 maximal dose received by the most exposed 2ccm of urinary bladder; EQD2 5 2-Gy equivalent dose.
Results Analysis of DUI during the followup period
Description of the study group and treatment characteristics Patients in the study group were aged 67.6 6.1 years, with following tumor characteristics: Gleason score: #6 22/88 (25.0%), 7 37/88 (42.0%), and $8 29/88 (33.0%); percent of positive cores: median 50 (range 10e100); prostate-specific antigen: median 10 ng/mL (range,
The course of DUI after treatment in relation to initial problems is presented as a prevalence rates during the second, the third, the fourth, and the fifth year of observation (Table 3). In this time frame, it seems that with longer followup proportion of patients with DUI is increasing (Table 3).
Table 3 Prevalence rates of alteration of urinary incontinence in Ljubljana Institute of Oncology study of late toxicity after high-dose-rate brachytherapy boost treatment for prostate cancer Year of followup
N
Major improvement (%)
Minor improvement (%)
No change (%)
Minor deterioration (%)
Major deterioration (%)
2nd year 3rd year 4th year 5th year
84 81 47 30
0 0 0 0
6 5 1 1
62 59 32 19
11 10 8 5
5 7 6 5
(0) (0) (0) (0)
(7.1) (6.2) (2.1) (3.3)
(73.8) (72.8) (68.1) (63.3)
(13.1) (12.3) (17.0) (16.7)
(6.8) (8.6) (12.8) (16.7)
B. Kragelj, L. Zaletel-Kragelj / Brachytherapy
Analysis of association between DUI and potential risk factors Analysis was carried out in 81 patients who completed 3 years of followup. In 17 of them (20.9%), DUI was evidenced. In the group of HDRB and supportive treatment factors CT-based imaging, higher D100PTV2 ; D-MEANurethra, and D2ccbladder volume were statistically significantly associated with higher rates of DUI (Table 4). In the group of patients’ characteristics, the vast majority of factors did not show statistically significant association with DUI, the only exception was diabetes (Table 5). All data necessary to perform multivariate analysis were present in 76/81 patients (93.8%). The results showed that among the HDRB and supportive treatment factors, only D2ccbladder volume remained statistically significantly associated with observed outcome. For each Gy (EQD2) received by the most exposed 2ccm of urinary bladder, the odds for DUI increased for about 14%. Among the patients’ characteristics, diabetes in multivariate analysis not merely retained its predictive value, but its value even increased (the odds for DUI were about 6.7 times higher for diabetic patients). In addition, increased initial nocturnal micturition frequency defined with three or more micturitions per night, that was marginally significant in univariate analysis, became statistically significant in multivariate analysis.
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The odds for DUI and therefore for additional deterioration of already at the start of EBRT þ HDRB existing urinary problems are about 3.7 times higher than in the rest of patients. All other results are presented in Table 6. Finally, for each patient, the risk of DUI was estimated on the basis of the LR equation (logit 5 4.268 þ 1.906 diabetes þ 1.313 initial nocturnal micturition frequency $3 þ 0.133 D2ccurinary bladder volume ). The values varied between 0.0331 and 0.8870, with the median value 0.1310. The value of area under receiver operating characteristic curve was 0.790, indicating fair predictive performance of the model. The best cut point was placed at value 0.20656 (true-positive rate: 13/16 or 0.813; false-positive rate: 16/60 or 0.267; true-negative rate: 44/60 or 0.733; false-negative rate: 3/ 16 or 0.188; positive predictive value: 13/29 or 0.448; negative predictive value: 44/47 or 0.936; and Youden index: 0.546). The estimates of the safe D2ccbladder volume for UI for patients with different characteristics considered in the LR model are presented in Table 7.
Discussion Results of the study indicate that on long term the occurrence, or in the case of already existing UI, further DUI is related not only to treatment itself and to treatment-related
Table 4 Results of univariate logistic regression analysis of association between deterioration of urinary incontinence and treatment factors in Ljubljana Institute of Oncology study of late toxicity after high-dose-rate brachytherapy boost treatment for prostate cancer 95% CI limits for OR Risk factor
Ntot
Nimplanted needles Planning imaging CT MRI Ninterventions 1 O1 PTV1 (mL) D100PTV1 (Gy) D90PTV1 (Gy) D100PTV2 (Gy) Vurethra (mL) D-MEANurethra (EQD2) (Gy) D90urethra volume ðEQD2Þ (Gy) D10urethra volume ðEQD2Þ (Gy) D1urethra volume ðEQD2Þ (Gy) D2ccbladder volume ðEQD2Þ (Gy) Duration of androgen deprivation !12 months $12 months
81 81
81
Ndet/Ncat (%)
OR
Lower
Upper
p
0.96
0.79
1.18
0.709
10/28 (35.7) 7/53 (13.2)
1.00 0.27
0.09
0.83
0.022
16/73 (21.9) 1/8 (12.5)
1.00 0.51 0.99 1.08 1.07 1.13 0.64 1.08 1.04 1.03 1.03 1.27
0.06 0.96 0.94 0.98 1.03 0.30 1.02 0.97 0.99 0.99 1.03
4.45 1.04 1.22 1.17 1.24 1.35 1.15 1.13 1.08 1.06 1.23
0.541 0.864 0.279 0.152 0.011 0.240 0.014 0.278 0.149 0.109 0.009
2/9 (22.2) 11/60 (18.3)
1.00 0.79
0.14
4.31
0.781
80 81 81 80 80 80 81 80 81 79 69
Ntot 5 total number of observations; Ndet 5 number of patients with deterioration; Ncat 5 number of patients within the category; OR 5 odds ratio; CI 5 confidence interval; PTV1 5 planning target volume 1; D100PTV1 5 minimal dose received by 100% of the PTV1; D90PTV1 5 minimal dose received by 90% of the PTV1; D100PTV2 5 minimal dose received by 100% of the PTV2; Vurethra 5 urethral volume; D-MEANurethra 5 mean urethral dose; D90urethra volume 5 minimal dose received by 90% of the urethra volume; D10urethra volume 5 minimal dose received by 10% of the urethra volume; D1urethra volume 5 minimal dose received by 1% of the urethra volume; D2ccbladder volume 5 maximal dose received by the most exposed 2ccm of urinary bladder; EQD2 5 2-Gy equivalent dose.
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Table 5 Results of univariate logistic regression analysis of association between deterioration of urinary incontinence and patients’ characteristics in Ljubljana Institute of Oncology study of late toxicity after high-dose-rate brachytherapy boost treatment for prostate cancer 95% CI limits for OR Risk factor Ntot Ndet/Ncat (%) OR
Lower
Age 81 0.94 Hypertension No 79 6/36 (16.7) 1.00 Yes 10/43 (23.3) 1.52 Diabetes No 78 12/70 (17.1) 1.00 Yes 4/8 (50.0) 4.83 Hyperlipidemia No 78 12/61 (19.7) 1.00 Yes 3/17 (17.6) 0.88 CVI No 79 16/69 (23.2) NA Yes 0/10 (0.0) NA Coronary insufficiency No 79 13/63 (20.6) 1.00 Yes 3/16 (18.8) 0.899 Anticoagulation treatment No 79 14/59 (23.7) 1.00 Yes 2/20 (10.0) 0.357 Initial nocturnal micturition frequency !3 81 8/53 (15.1) 1.00 $3 9/28 (32.1) 2.67 Initial urinary incontinence No 81 12/63 (19.0) 1.00 Yes 5/18 (27.8) 1.64 Initial urinary obstruction No 78 3/28 (10.7) 1.00 Yes 13/50 (26.5) 2.93
0.85
Upper 1.03
0.156
4.76
0.470
1.06
22.08
0.042
0.22
3.54
0.851
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Table 6 Results of multivariate logistic regression analysis of association between deterioration of urinary incontinence and selected treatment factors and patients’ characteristics in Ljubljana Institute of Oncology study of late toxicity after high-dose-rate brachytherapy boost treatment for prostate cancer (N 5 76) 95% CI limits for OR
p
0.49
/ /
-
/ /
0.22
3.58
0.867
0.07
1.73
0.201
0.89
7.95
0.079
0.49
5.47
0.425
0.76
11.34
0.120
Ntot 5 total number of observations; Ndet 5 number of patients with deterioration; Ncat 5 number of patients within the category; OR 5 odds ratio; CI 5 confidence interval; NA 5 not applicable; CVI 5 history of cerebrovascular insult/peripheral deep venous thrombosis.
parameters, but it seems that patients’ characteristics are equally important and predictive. The dose received by the bladder base was more or less neglected in studies that tried to relate dosimetric factors of HDRB and LUT (3, 6, 9, 13, 14) and was mostly unused as a normal-dose constraint in the planning process (3,9,13,14,27e29). Two recent studies, the Hathout study of LDRPB (30) and the Mazeron study of advanced cervical cancer treatment with pulsed dose rate uterovaginal brachytherapy and EBRT (31), stressed the link between LUT and dose received by the bladder base. In the Hathout study (30), the minimal dose received by 2ccm of the bladder neck was found to be the strongest predictor for acute and LUT defined by I-PSS. Bladder neck dose was more important also in relation to D2ccbladder volume that loses its significance as independent predictor for LUT in multivariate analysis. It is unclear whether these findings could be considered for EBRT þ HDRB and UI as the observed outcome. However, UI was the observed outcome in the
Risk factor
b
OR
Diabetes No 1.00 Yes 1.906 6.73 Initial nocturnal micturition frequency !3 1.00 $3 1.313 3.72 D2ccbladder volume ðEQD2Þ (Gy) 0.133 1.14 Constant 4.268
Lower
Upper
p
0.96 1.17
1.57 38.56
0.032
1.03 1.03
13.04 1.26
0.045 0.010
OR 5 odds ratio; CI 5 confidence interval; D2ccbladder volume 5 maximal dose received by the most exposed 2ccm of urinary bladder; EQD2 5 2Gy equivalent dose.
Mazeron study (31): for the group of patients with D2ccbladder volume close to bladder neck, a significant correlation between the D2ccbladder volume and incontinence that necessitate pads was reported. Together with stated importance of dose to the bladder base a common point with our findings is also a quite similar proposed threshold sum EQD2 dose of EBRT and D2ccbladder volume dose $75 Gy. According to American Brachytherapy Society guidelines, significant urinary symptoms are a relative contraindication to EBRT þ HDRB, but patients should possibly expect worsening of urinary function (27). Our study confirmed that statement. The correlation between baseline urinary symptoms and LUT was evidenced for LDRPB (32e34) and EBRT (35). However, urinary problems at the beginning of the treatment not merely correlated to LUT but actually increased the risk of further deterioration of urinary problems. This phenomenon seems to be first reported in our study. Comorbidities except transurethral resection were not regularly emphasized in the studies of LUT after EBRT þ HDRB. According to our study, diabetes seems to be more important predictor for UI than dosimetric Table 7 The estimates of the safe doses for the most exposed 2ccm of urinary bladder (D2ccbladder volume ðEQD2Þ ) for deterioration of urinary incontinence (DUI) for patients with different characteristics considered in the logistic regression model Initial nocturnal Combination of micturition Estimate characteristics Diabetes frequency of the safe D2ccbladder volume ðEQD2Þ dose 1 2 3 4
No No Yes Yes
!3 $3 !3 $3
EQD2 5 2-Gy equivalent dose.
21.9 Gy 12.0 Gy 7.6 Gy No safe dose for DUI
B. Kragelj, L. Zaletel-Kragelj / Brachytherapy
parameters and other patients’ characteristics. Diabetes by itself was found as a strong predictor for UI (36, 37) and was identified as a predictor of LUT concerning frequency and dysuria after EBRT for prostate cancer (38, 39). There are no data about the predictive role of diabetes for late UI after EBRT þ HDRB. According to our experience, comorbidity including diabetes is important predictor for LUT. Limitations of the study First, one could argue that instead of internationally validated questionnaire, an IOL in-house made questionnaire was used as a study instrument. However, at IOL, this instrument was used already for several years and replacing the questionnaire would affect the comparability of responses in time. Second, in our study, UI was not quantified in the sense of scoring, as it is possible by validated healthrelated quality-of-life instruments. Instead of that, UI was classified into standard toxicity grades, and as a measure of deterioration, only a two-stage system was used. With this simplified system, a rather robust assessment of UI deterioration was achieved. Statistically significant correlation between DUI and patient-reported micturition quality confirmed its validity. However, small, but for quality-oflife perhaps important changes, may be missed. Yet with the use of self-administered questionnaires that take into account different expressions of UI a reliable, and patient-oriented information was gathered. Finally, a relation to DUI was searched only in dose-volume parameters of brachytherapy treatment, and the impact of dose-volume histogram parameters of EBRT was neglected. That also EBRT component of combined treatment has perhaps important effect on LUT is suggested from studies comparing different combinations of radiation treatment (5,40). However, the aim of the study was to optimize brachytherapy part of the treatment, some for brachytherapy important data may be obscured by adding EBRT data, and for that reason, EBRT data were omitted. The importance of the study results for clinical practice Study discloses parameters involved in the development of DUI. Taking account of diabetes and nocturia as risk factors, three dose constraints for the total EQD2 as the sum of HDRB urinary D2ccbladder volume and mean EBRT prostate EQD2 can be suggested: 72 Gy for patients without risk factors, with additional diabetes 57 Gy, and for patients with high initial nocturnal micturition frequency 62 Gy. It seems that in patients with both risk factors, it is impossible to retain this low risk of DUI (!6%) and to them perhaps other forms of prostate cancer treatment should be offered. Here, we can stress the strengths of the study. First, the concept of dealing with dose restrictions in connection with patients’ characteristics is not a common practice in radiotherapy. In our case, consideration of patient’s characteristics improves the predictive value of merely D2ccbladder volume :
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The estimates of safe doses for D2ccbladder volume are therefore given in conjunction with information on diabetes status and nocturnal micturition frequency. Suggested restraints are indicated with fair predictive performance of the model and high negative predictive value, which allows HDRB with low risk of UI. Second, the urinary bladder base is not universally accepted as an organ at risk in HDRB (30). The identified relationship between UI and urinary bladder base dose suggests that the latter should be considered in the planning procedure. Contouring of the lowest 1.5 cm of urinary bladder seems to be sufficient to get reliable information about the dose to its most exposed part. Possibilities for further research in the field It is unclear whether detrusor overactivity involved in the emergence of UI early after LDRPB (41) could be the cause for late UI after LDRPB and EBRT þ HDRB. Urodynamic studies are needed to elucidate pathophysiology of UI (42) and also to better disclose patients at increased risk for UI. The predictive role of urinary D2ccbladder volume for UI suggests that bladder base contains structures crucial for the emergence of UI. Bladder neck and trigone area were implicated as critical structures for LDRPB and cervical cancer brachytherapy. However, critical structure for UI after EBRT þ HDRB is still needed to be identified.
Conclusion The present study discloses the impact of characteristics of patients as well as particular structures and dosimetric parameters in the emergence of LUT. Diabetes, nocturnal micturitions, and the D2ccbladder volume are identified as independent predictors for DUI. Taking account of these parameters a set of dose constraints is suggested to reduce the DUI. However, additional studies are needed not only to validate suggested dose constraints but also to improve understanding of underlying pathophysiology and to more precisely identify structures involved in the process of late UI. References [1] Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate cancer survivors. N Engl J Med 2008;358:1250e1256. [2] Vargas CE, Martinez AA, Boike TP, et al. High-dose irradiation for prostate cancer via high-dose-rate brachytherapy boost: results of a phase I to II study. Int J Radiat Oncol Biol Phys 2006;66:416e423. [3] Ghadjar P, Rentsch CA, Isaak B, et al. Urethral toxicity vs. cancer control- lessons to be learned from high-dose rate brachytherapy combined with intensity-modulated radiation therapy in intermediateand high-risk prostate cancer. Brachytherapy 2011;10:286e294. [4] Martınez-Monge R, Moreno M, Ciervide R, et al. External-beam radiation therapy and high-dose rate brachytherapy combined with long-term androgen deprivation therapy in high and very high prostate cancer: preliminary data on clinical outcome. Int J Radiat Oncol Biol Phys 2012;82:469e476.
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[5] Mohammed N, Kestin L, Ghilezan M, et al. Comparison of acute and late toxicities for three modern high-dose radiation treatment techniques for localized prostate cancer. Int J Radiat Oncol Biol Phys 2012;82:204e212. [6] Hsu IC, Hunt D, Straube W, et al. Dosimetric analysis of radiation therapy oncology group 0321: the importance of urethral dose. Pract Radiat Oncol 2014;4:27e34. [7] Smith DP, King MT, Egger S, et al. Quality of life three years after diagnosis of localised prostate cancer: population based cohort study. BMJ 2009;339:b4817. [8] Pinkawa M, Fischedick K, Treusacher P, et al. Dose-volume impact in high-dose-rate Iridium-192 brachytherapy as a boost to external beam radiotherapy for localized prostate cancer-a phase I study. Radiother Oncol 2006;78:41e46. [9] Duchesne GM, Das R, Toye W. Dose distribution and morbidity after high dose rate brachytherapy for prostate cancer: influence of V150 and V200 parameters. Australas Radiol 2002;46:384e389. [10] Galalae RM, Kovacs G, Schultze J, et al. Long-term outcome after elective irradiation of the pelvic lymphatics and local dose escalation using high-dose-rate brachytherapy for locally advanced prostate cancer. Int J Radiat Oncol Biol Phys 2002;52:81e90. [11] Astr€ om L, Pedersen D, Mercke C, et al. Long-term outcome of high dose rate brachytherapy in radiotherapy of localised prostate cancer. Radiother Oncol 2005;74:157e161. [12] Luo HL, Fang FM, Kang CH, et al. Can high-dose-rate brachytherapy prevent the major genitourinary complication better than external beam radiation alone for patients with previous transurethral resection of prostate. Int Urol Nephrol 2013;45:113e119. [13] Hashimoto Y, Akimoto T, Iizuka J, et al. Correlation between the changes in the EPIC QOL scores and the dose-volume histogram parameters in high-dose-rate brachytherapy combined with hypofractionated external beam radiation therapy for prostate cancer. Jpn J Clin Oncol 2015;45:81e87. [14] Ishiyama H, Kitano M, Satoh T, et al. Genitourinary toxicity after high-dose-rate (HDR) brachytherapy combined with hypofractionated external beam radiotherapy for localized prostate cancer: an analysis to determine the correlation between dose-volume histogram parameters in HDR brachytherapy and severity of toxicity. Int J Radiat Oncol Biol Phys 2009;75:23e28. [15] D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969e974. [16] Roach M 3rd, Marquez C, Yuo HS, et al. Predicting the risk of lymph node involvement using the pre-treatment prostate specific antigen and Gleason score in men with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1994;28:33e37. [17] Cox JD, Stetz JA, Pajak TF. Toxicity criteria of the radiation therapy oncology group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341e1346. [18] Marks LB, Carroll PR, Dugan TC, Anscher MS. The response of the urinary bladder, urethra, and ureter to radiation and chemotherapy. Int J Radiat Oncol Biol Phys 1995;31:1257e1280. [19] Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS;. Publish Date: August 9, 2006. Available at: http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed December 12, 2015. [20] Skala M, Rosewall T, Dawson L, et al. Patient-assessed late toxicity rates and principal component analysis after image-guided radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys 2007;68:690e698. [21] Storey MR, Pollack A, Zagars G, et al. Complications from radiotherapy dose escalation in prostate cancer: preliminary report of a randomized trial. Int J Radiat Oncol Biol Phys 2000;48:635e642. [22] Hosmer DW, Lemeshow S. Applied logistic regression. New York (NY): John Wiley&Sons; 2000.
-
(2016)
-
[23] McNeil BJ, Keeler E, Adelstein JS. Primer on certain elements of medical decision making. N Engl J Med 1975;293:211e215. [24] Bradley GW, editor. Disease, diagnosis and decisions. Chichester: John Wiley&Sons; 1993. [25] Kallin Westin L. Receiver operating characteristic (ROC) analysis: valuating discriminance effects among decision support systems. Umea: Umea University, Department of Computing Science; 2001. [26] Schisterman EF, Perkins NJ, Liu A, Bondell H. Optimal cut-point and corresponding Youden index to discriminate individuals using pooled blood samples. Epidemiology 2005;16:73e81. [27] Yamada Y, Rogers L, Demanes DJ, et al. American brachytherapy society consensus guidelines for high-dose-rate prostate brachytherapy. Brachytherapy 2012;11:20e32. [28] Hoskin PJ, Colombo A, Henry A, et al. GEC/ESTRO recommendations on high dose rate afterloading brachytherapy for localised prostate cancer: an update. Radiother Oncol 2013;107:325e332. [29] Zwahlen DR, Andrianopoulos N, Matheson B, et al. High-dose-rate brachytherapy in combination with conformal external beam radiotherapy in the treatment of prostate cancer. Brachytherapy 2010;9:27e35. [30] Hathout L, Folkert MR, Kollmeier MA, et al. Dose to the bladder neck is the most important predictor for acute and late toxicity after low-dose-rate prostate brachytherapy: indications for establishing new dose constraints for treatment planning. Int J Radiat Oncol Biol Phys 2014;90:312e319. [31] Mazeron R, Dumas I, Rivin E, et al. D2cm3/DICRU ratio as a surrogate of bladder hotspots localizations during image-guided adaptive brachytherapy for cervical cancer: assessment and implications in late urinary morbidity analysis. Brachytherapy 2015;14:300e307. [32] Steggerda MJ, Witteveen T, van den Boom F, Moonen LM. Is there a relation between the radiation dose to the different sub-segments of the lower urinary tract and urinary morbidity after brachytherapy of the prostate with J-125 seeds. Radiother Oncol 2013;109:251e255. [33] Malick S, Azzouzi R, Cormier L, et al. Urinary morbidity after 125I brachytherapy of the prostate. BJU Int 2003;92:555e558. [34] Wehle MJ, Lisson SW, Buskirk SJ, et al. Prediction of genitourinary tract morbidity after brachytherapy for prostate adenocarcinoma. Mayo Clin Proc 2004;79:314e317. [35] Barnett GC, De Meerleer G, Gulliford SL, et al. The impact of clinical factors on the development of late radiation toxicity: results from the Medical Research Council RT01 Trial (ISRCTN 47772397). Clin Oncol 2011;23:613e624. [36] Danforth KN, Townsend MK, Curhan GC, et al. Type 2 diabetes mellitus and risk of stress, urge and mixed urinary incontinence. J Urol 2009;181:193e197. [37] Brown JS, Vittinghoff E, Lin F, et al. Prevalence and risk factors for urinary incontinence in women with type 2 diabetes and impaired fasting glucose: findings from the National Health and Nutrition Examination Survey (NHANES) 2001e2002. Diabetes Care 2006;29: 1307. [38] Mathieu R, Arango JDO, Beckendorf V, et al. Nomograms to predict late urinary toxicity after prostate cancer radiotherapy. World J Urol 2014;32:743e751. [39] Yahya N, Ebert MA, Bulsara M, et al. Dosimetry, clinical factors and medication intake influencing urinary symptoms after prostate radiotherapy: an analysis of data from the RADAR prostate radiotherapy trial. Radiother Oncol 2015;116:112e118. [40] Lawton CA, Yan Y, Lee WR, et al. Long-term results of an RTOG phase II trial (00-19) of external-beam radiation therapy combined with permanent source brachytherapy for intermediate-risk clinically localized adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 2012;82:e795ee801. 41 Blaivas JG, Weiss JP, Jones M. The pathophysiology of lower urinary tract symptoms after brachytherapy for prostate cancer. BJU Int 2006; 98:1233e1237. 42 Rosier PF, Giarenis I, Valentini FA, et al. Do patients with symptoms and signs of lower urinary tract dysfunction need a urodynamic diagnosis? ICI-RS 2013. Neurourol Urodyn 2014;33:581e586.