Temporary prostate brachytherapy alone or as boost: Single-institution experience on dose-response assessment focusing on sphincter-related urinary toxicity

Abstract

Purpose

To investigate the relation between radiation dose to organs at risk (OARs), including internal and external urethral sphincters (IUS, EUS), and the occurrence of urinary toxicity in patients treated with high-dose-rate (HDR) and pulsed-dose-rate (PDR) prostate brachytherapy.

Material and methods

Two-hundred eighty patients treated with HDR or PDR brachytherapy as monotherapy or boost after external beam radiation therapy (EBRT) between 2012 and 2020 were analyzed retrospectively. Prostate, urethra, bladder, rectum, IUS, and EUS were contoured on transrectal ultrasound (TRUS). Physical dose-volume histograms (DVHs) were converted to EQD₂ (α/β = 3 Gy) and for PDR, corrected for incomplete repair. Urinary toxicity (dysuria, incontinence) was graded using LENT/SOMA scale. Dose-response relationships were assessed with Barnard’s test, while survival and toxicity outcomes were analyzed using Kaplan-Meier and log-rank tests.

Results

Of the 280 patients considered (median follow-up, 92 months; range, 1-146 months), 29 received brachytherapy as monotherapy and 251 as boost after EBRT. Five-year overall survival (OS), disease-free estimate (DFE), local recurrence rate, and biochemical disease-free estimate (bDFE) were 89%, 86%, 3.6%, and 81% for brachytherapy alone, and 85%, 86%, 2.9%, and 85% for EBRT plus brachytherapy, respectively. The cumulative incidence of grade 3 dysuria and incontinence was 3% and 7% at two-years, respectively. Higher EUS dose (D_0.5cm3 > 102-106 Gy) was associated with increased dysuria and incontinence (p ≤ 0.03), while IUS dose (D_0.1cm3 > 83 Gy) was correlated with increased dysuria (p = 0.04).

Conclusions

Higher sphincter doses, particularly EUS exposure, were significantly associated with urinary toxicity. The IUS primarily influenced dysuria. Our results highlight the importance of considering both sphincters as individual organs at risk, and support the implementation of specific dose constraints to minimize urinary side effects.

Purpose

Approximately one in six men in Europe will develop prostate cancer in the course of his life, whereas globally, prostate carcinoma is the second most common malignant tumor in men and fifth cause of cancer-related death [1-3]. Treatment is typically administered with curative intent and, among the available options, brachytherapy is a well-established and effective modality. By placing the radiation source directly into the tumor area, brachytherapy achieves high level of precision, minimizing exposure to surrounding organs at risk (OARs) [4-8].

Apart from high local control rates of up to 99% depending on tumor stage, side effects in prostate brachytherapy mainly affect the lower urinary tract [9]. Epithelial tissues, such as the urothelium of the bladder and urethra are particularly radiosensitive. In the bladder, radiation may cause urothelial thinning, inflammation, and ulceration, whereas in the urethra, late effects, including strictures and fibrotic re-modeling may be observed. The extent of these changes is highly dose-dependent [10-15].

In recent years, the internal (IUS) and external (EUS) urinary sphincters have raised attention in dose-response assessments. Due to their close anatomical proximity to the prostate, both structures receive a significant radiation dose during prostate brachytherapy and radiation therapy in general. As central components of the continence mechanism, damage to these sphincters may lead to a considerable reduction in the patient’s quality of life [16, 17]. In this respect, Register et al. demonstrated that higher radiation doses to the EUS and IUS during permanent low-dose-rate (LDR) brachytherapy using iodine-125 seeds, are associated with increased urogenital toxicity. Their analysis was based on MRI-guided contouring of these structures in patients with intermediate-risk prostate cancer [18]. However, to the best of our knowledge, data on the corresponding impact on sphincter-related side effects from temporary pulsed-dose-rate (PDR) or high-dose-rate (HDR) brachytherapy techniques are not available.

To address this issue, we conducted a retrospective dose-response analysis for a large cohort of 280 patients treated with temporary prostate brachytherapy as monotherapy or boost after external beam radiation therapy (EBRT). The objective was to assess potential correlations between dose parameters reported for the prostate, urethra, bladder, and especially the urinary sphincters with clinically observed urinary side effects, and to identify potential dose thresholds associated with increased organ-specific toxicity. This may support the patient-specific optimization and adaptation of clinically delivered dose distributions to further improve both efficacy and safety of temporary prostate brachytherapy.

Material and methods

Implantation workflow

At our institution, temporary prostate brachytherapy starts with transperineal implantation of metal needles into the prostate, with patients under either spinal or general anesthesia, placed in dorsal lithotomy position. For this procedure, a perineally positioned template with a grid spacing of 5 mm in both horizontal and vertical directions is used to ensure precise needle placement. The intended implantation positions of needles are jointly defined and documented by a senior physician and medical physicist based on the patient’s individual anatomy; implantation is guided by means of high-resolution biplanar transrectal ultrasound (TRUS; GE HealthCare, Chicago, Illinois, USA) using a dedicated stepper device. At the end of the procedure, all needles are shifted cranially under sagittal ultrasound guidance in order to locate the needle tips approximately 8-9 mm beyond the prostate base, as defined on ultrasound. Finally, axial ultrasound images are acquired with a slice spacing of 5 mm using the stepper device. These stacked axial images form a three-dimensional (3D) ultrasound volume employed for subsequent treatment planning.

Treatment planning

Using the Oncentra Brachy treatment planning system (Elekta AB, Sweden), a medical physicist first reconstructed the needle paths based on intraoperative needle position documentation. Then, the senior physician delineated the OARs comprising bladder, rectum, and prostatic urethra, including a 5 mm craniocaudal extent immediately adjacent to the prostate as well as planning target volume (PTV) [19]. PTV was identical to clinical target volume (CTV) that included the prostate and, if indicated, seminal vesicles, without any additional safety margins being applied. Internal and external urinary sphincters were additionally delineated on ultrasound images. Internal urinary sphincter (IUS) was contoured starting at the verumontanum level with a diameter corresponding to that of the urethra, and was extended cranially in shape of a funnel into the bladder neck [18, 20]. External urinary sphincter (EUS) was delineated starting near the verumontanum and extending approximately 5-10 mm beyond the apical end of the prostate [18, 20], as illustrated in Figure 1.

Fig. 1.

Exemplary three-dimensional delineation of the prostate (orange transparent), rectum (dark green), bladder (yellow), urethra (light green), seminal vesicles (purple), internal urethral sphincter (transparent dark blue), and external urethral sphincter (transparent cyan) performed by the Oncentra Brachy treatment planning system

Based on these procedures, manual forward planning was used to define dwell positions and times of iridium-192 afterloader source, considering an optimization of dose-volume-histogram (DVH) parameters. The aim was to achieve a PTV coverage with the prescribed dose of at least > 90% while keeping D_2cm3 (dose received by the most exposed 2 cm³ of the structure) of the rectum and bladder below 75 Gy and 85 Gy, respectively, also given potential pre-irradiations (dose summation in EQD₂, with α/β = 3 Gy). For the urethra, a dose constraint of 130% of the prescribed brachytherapy dose on 0.1 cm³ was deemed. Dose to urinary sphincters was only reported but featured no constraints.

Treatment regimes

Treatment delivery was conducted using either PDR or HDR, depending on availability. For definitive brachytherapy, patients received a fractionation of either 4 × 9.0-9.5 Gy (HDR) delivered in two sessions of two irradiations each, or 100 × 0.7 Gy (PDR) pulsed hourly irradiations delivered in two sessions of 50 pulses each, respectively. The two sessions were administered with a time gap of about three weeks.

For brachytherapy performed as boost after external beam radiation therapy, the prescribed fractionation scheme was 2 × 7.0-9.5 Gy for HDR (depending on the pre-irradiation; one fraction delivered in the afternoon and one in the following morning), and 50 × 0.7 Gy hourly pulsed irradiations for PDR brachytherapy. The previous EBRT treatment was conducted by means of intensity modulation radiation therapy (IMRT) or volumetric intensity modulated radiation therapy (VMAT), with a median total dose of 50.4 Gy (range, 38.5-54 Gy) and fraction dose of 1.8 Gy (range, 1.8-2.75 Gy) delivered daily, five days per week. Clinical target volume (CTV) for EBRT was defined as the entire prostate gland and seminal vesicles, with safety margins of 5-10 mm in all directions. For high-risk patients, CTV also included the internal iliac, external iliac, common iliac, and pre-sacral lymph node regions, while PTV resulted from CTV with an additional margin of 5-15 mm. Please note that patients receiving a brachytherapy boost underwent EBRT either at our institution or at external referring centers. Consequently, planning CT acquisition and treatment planning were performed using institution-specific CT scanners and treatment planning systems. However, all EBRT treatments were based on computed tomography imaging. For subsequent brachytherapy boost, treatment planning was conducted as described above considering the afore-mentioned dose constraints for the rectum and bladder of a D_2cm3 below 75 Gy and 85 Gy (EQD₂; including pre-irradiation), respectively.

Analysis of efficacy and side effects

The primary objective of the present study was to investigate the sphincter-related urinary toxicity and correlations with corresponding dose-volume parameters. Therefore, we focused on dysuria and incontinence as side effects, which were documented and assessed according to the toxicity grading system outlined by LENT/SOMA [21], along with prostate-specific antigen (PSA) value at each follow-up visit. Note that our institutional follow-up protocol after brachytherapy consists of regular visits at intervals of 3 months after treatment for the first 24 months and annually thereafter.

The efficacy of the treatment was evaluated by analyzing overall survival, disease-free estimate, biochemical disease-free estimate (defined as a PSA increase of > 2 ng/ml above the nadir [Phoenix definition]), and cumulative local recurrence rate. Both efficacy and toxicity were estimated using the Kaplan-Meier method and by calculating the corresponding prevalence of side effects. A SciPy-based Fisher’s exact test [22] was used to analyze potential differences in patient outcomes between HDR and PDR as well as between boost and brachytherapy monotherapy, with significance level set at 5%. Please note that, in accordance with the Bavarian hospital law, ethics approval by our local institution was not required for performing the presented retrospective analyses.

Dosimetric analysis and statistical evaluation

To analyze correlations between the afore-mentioned side effects and treatment efficacy as well as dose-volume parameters of the relevant anatomical structures, DVHs generated by the treatment planning system (initially based on physical dose) were converted into biologically effective DVHs, i.e., iso-effective doses to 2 Gy fractions (EQD₂), to account for differences in fractionations. For this purpose, an α/β ratio of 3 Gy was used for the prostate, sphincters, urethra, and bladder.

For PDR brachytherapy, an additional correction accounting for incomplete sub-lethal damage repair between pulses with a repair half-life of 1.9 h for the prostate and 0.3 h for the bladder, urethra, IUS, and EUS was applied in the EQD₂ calculation [23, 24]. For patients receiving brachytherapy as boost following EBRT, dose contributions from EBRT to the respective structures were also converted to EQD₂ using the same α/β ratios. Although in CT-based EBRT planning, a direct delineation of the urethra and sphincters was generally not possible, we assumed that both the urethra and sphincters received a homogeneous dose equal to the dose prescribed to the prostate for EBRT. DVHs generated for EBRT and brachytherapy, both converted to EQD₂, were then summed for each structure to provide a conservative estimate of the total biologically effective dose received.

To assess potential correlations between the observed toxicities or endpoints and calculated doses for each anatomical structure, Barnard’s test was used to analyze the significance of cohort separations by specific dose values. For each investigated dose parameter, threshold values for every structure were systematically varied from the minimum to the maximum observed dose in increments of 0.1 Gy. For each threshold, patients were dichotomized according to whether the respective dose parameter exceeded the threshold, and a 2 × 2 contingency table was constructed based on the presence or absence of the investigated endpoint. Subsequently, Barnard’s test was applied to each contingency table. Threshold associated with the smallest p-value was selected as the candidate dose level providing the strongest cohort separation. Statistical significance was evaluated at 5% significance level. Since multiple candidate thresholds were estimated for each dose parameter, this procedure represented an exploratory, data-driven threshold search. Since the objective was hypothesis generation rather than confirmatory hypothesis testing, no formal adjustment for multiple testing was performed. Consequently, the identified threshold values and associated p-values should be interpreted with caution, as they require validation in independent datasets. For this dose-response analysis, we considered dose parameters D_{0.1 cm3} and D_0.5cm3 for the IUS, EUS, and urethra, and D_10% and D_30% for the urethra. Furthermore, D_2cm3 was deemed for the bladder, and D₉₀ and D₉₅ for the prostate. Dx indicated the dose received by the most exposed x cm³ or x % of the structure, respectively.

Results

Patient characteristics

The current study included 280 consecutive patients treated in our institution between 2012 and 2020 with temporary prostate brachytherapy according to the above-described workflow, with a median follow-up of 92 months (range, 1-146 months). Of these, 29 patients received brachytherapy alone (HDR, n = 10; PDR, n = 19) and 251 patients received brachytherapy as boost following EBRT (HDR, n = 173; PDR, n = 78). The median age of patients was 73 years (range, 47-87 years), and the median initial PSA value was 10.98 ng/ml (range, 0.6-4,048 ng/ml). In terms of risk stratification according to D’Amico, 179 patients (64%) had high-risk, 77 patients (28%) intermediate-risk, and 24 patients (9%) low-risk prostate cancer [25]. At the time of diagnosis, 23 patients (8%) already presented with lymph node metastases. The patient characteristics are presented in Table 1.

Table 1.

Characteristics of patients (n = 280), separated by treatment regime (PDR, HDR) with regards to age, initial PSA, Gleason’s score, D’Amico risk group, initial lymph node metastasis, and whether or not they received hormone therapy

Parameter		All patients (N = 280)	PDR (n = 97)	HDR (n = 183)
Age at brachytherapy (years)
	Median	73	73	73
	Range	47-87	52-83	47-87
Initial PSA (ng/ml)
	Median	10.98	8.89	12.20
	Range	0.6-4,048	1.36-1,036	0.6-4,048
Gleason’s score, n (%)
	5 or 6	61 (22)	26 (27)	35 (19)
	7	107 (38)	39 (40)	68 (37)
	8	47 (17)	22 (23)	25 (14)
	9 or 10	65 (23)	10 (10)	55 (30)
D’Amico risk group, n (%)
	Low-risk	24 (9)	15 (15)	9 (5)
	Intermediate-risk	77 (28)	27 (28)	50 (27)
	High-risk	179 (64)	55 (57)	124 (68)
Initial lymph node metastasis, n (%)		23 (8)	4 (4)	19 (10)
Hormone therapy, n (%)
	Yes	136 (49)	45 (46)	91 (50)
	No	144 (51)	52 (54)	92 (50)

Side effects

The analysis of side effects revealed that the cumulative incidence of dysuria of any grade was 29% after one year, and reached a plateau by the second year at 36% (105 patients). However, the cumulative incidence of dysuria grade 2 and 3 was only 8% and 3% at two years, respectively, as shown in Figure 2. When stratified by treatment modality, no significant differences were observed between HDR or PDR treatments (p > 0.1). Likewise, the occurrence of grade 3 dysuria did not differ between patients receiving definitive brachytherapy (1 affected patient) and brachytherapy as boost (7 patients, p = 0.59). However, in this respect, the small number of only 29 patients receiving sole brachytherapy treatment has to be taken into account.

Fig. 2.

A) Cumulative incidence of dysuria grade 2 and 3, separated by B) HDR and PDR treatment regime. C) Cumulative incidence of incontinence grade 2 and 3, separated by D) HDR and PDR treatment regime is also shown

Incontinence of grade 2 and 3 was found to be 10% and 5% at one year as well as 12% and 7% at two years, respectively (Figure 2). When separated by treatment type, again no significant differences between HDR and PDR treatments were observed. Similarly, the occurrence of grade 3 incontinence did not differ between patients receiving definitive brachytherapy (1 patient) and brachytherapy as boost (15 patients, p = 0.71).

Table 2 summarizes in detail the identified dose thresholds associated with increased incidence of the investigated urinary side effects (dysuria and incontinence of grade ≥ 2). In terms of the EUS, a significantly enhanced dysuria (18.7% vs. 7.5%, p = 0.004) and incontinence (27.9% vs. 17.5%, p = 0.03) was observed for a D_0.5cm3 exceeding 102-106 Gy. Also, an increased incidence of dysuria (16.4% vs. 8.6%, p = 0.03) was seen for a D_0.1cm3 > 112 Gy. In contrast, for the IUS, no dosimetric association with increased rates of incontinence was found, whereas a D_0.1cm3 > 83 Gy resulted in a significantly increased dysuria (15.1% vs. 5.9%, p = 0.04).

Table 2.

Dose-response relations observed for dysuria and incontinence of grade ≥ 2. For each considered dosimetric parameter, the threshold separating the entire patient cohort with the largest statistical power (i.e., the lowest p-value) is shown. The “Affected patients” column indicates the number of patients with the respective event out of the total number of patients below and above the corresponding dose threshold, respectively. Significant numbers are printed bold

Structure	Dose value	Dysuria				Incontinence
		Thresh. (Gy)	Affected patients (events/total)		p-value	Thresh. (Gy)	Affected patients (events/total)		p-value
			Below thresh.	Above thresh.			Below thresh.	Above thresh.
EUS
	D0.1cm3	112.3	11/128	25/152	0.030	130.2	39/204	19/76	0.160
	D0.5cm3	101.9	11/146	25/134	0.004	106.3	34/194	24/86	0.030
IUS
	D0.1cm3	83.3	4/68	32/212	0.040	90.4	26/130	32/150	0.430
	D0.5cm3	74.7	7/88	29/192	0.060	78.7	28/143	30/137	0.340
Urethra
	D0.1cm3	112.4	19/188	17/92	0.030	121.5	52/263	6/17	0.100
	D0.5cm3	110.5	27/250	9/30	0.020	110.4	48/246	10/34	0.120
	D10%	109.0	14/152	22/128	0.030	120.8	52/264	6/16	0.070
	D30%	112.0	27/251	9/29	0.020	115.5	52/264	6/16	0.070
Bladder
	D2cm3	68.5	19/183	17/97	0.060	70.5	44/219	14/61	0.330
Prostate
	D90	102.1	12/169	24/111	0.001	102.2	27/172	31/108	0.006
	D95	96.7	19/194	17/86	0.020	97.8	39/226	19/54	0.006

Notably, all volume doses (D_0.1cm3, D_0.5cm3, D_10%, and D_30%) analyzed for the urethra yielded higher rates of dysuria (but not incontinence) by exceeding certain dose constraints, as listed in Table 2. For the bladder, no dose constraint for the commonly reported D2 ccm parameter was found, whereas a prostate D₉₀ > 102 Gy was correlated to increased dysuria and incontinence rates.

Efficacy

Given the presented patient cohort and the small number of patients receiving sole brachytherapy, the Kaplan-Meier estimator overall survival (OS) and disease-free estimate (DFE) at five years resulted in 85% and 86% for patients receiving brachytherapy as boost after EBRT as well as 89% and 86% for patients receiving definitive brachytherapy, respectively. The cumulative local recurrence rate was 3% at five years (2.9% for brachytherapy after EBRT and 3.6% for brachytherapy alone). Specifically, local recurrences were observed in one patient at two years, and seven patients at five years after brachytherapy. In addition, biochemical disease-free estimate (bDFE) according to Kaplan-Meier was 85% at five years for patients treated with EBRT plus brachytherapy boost and 81% for sole brachytherapy, respectively. In these reports, partly large confidence intervals observed for brachytherapy alone (illustrated in Figure 3) due to the small number of examined patients has to be noted. Considering all the assessed metrics, no statistically significant differences between PDR and HDR treatments were noted (p > 0.1). The corresponding results are graphically illustrated in Figure 3.

Fig. 3.

Kaplan-Meier estimator for overall survival, separated by treatment modality: brachytherapy (BT) as boost after external beam radiation therapy (EBRT) vs. brachytherapy alone, (A) and separated by dose rate regime (B), for disease-free survival separated by treatment modality (C) and separated by dose rate regime (D), cumulative local recurrence separated by treatment modality (E), as well as biochemical disease-free survival separated by treatment modality (F). Shaded areas refer to the 95th percent confidence interval

According to D’Amico classification, low-, intermediate-, and high-risk OS and bDFE at five years resulted in 95.8%, 94.5%, and 80.1%, and 91.1%, 90.4%, and 81.6%, respectively. The cumulative local recurrence rate at five years was 4.3% (1 affected patient), 0%, and 4.1% for low-, intermediate-, and high-risk patients, respectively, whereby the small number of patients included in the low-risk group was associated with increased statistical uncertainty.

Given the performed dose-response analysis, prostate D₉₀ < 97-98 Gy was statistically significantly associated with reduced overall survival (75.2% vs. 92.9%, p = 0.02) and biochemical disease-free estimate (82.8% vs. 92.3%, p = 0.04). In addition, prostate D₉₅ < 92-93 Gy was statistically significantly (p < 0.02) associated with reduced overall survival (73.2% vs. 92.5%) and biochemical disease-free estimate (81.8% vs. 92.7%). No corresponding correlations were found for disease-free estimate, and no examinations were performed for local recurrences due to the very low absolute number of only seven recurrences observed in the entire cohort. The observed dose-response relations are shown in Table 3.

Table 3.

Dose-response relations observed for disease-free estimate, overall survival, and biochemical disease-free estimate. For each dosimetric parameter considered, the threshold separating the entire patient cohort with the largest statistical power (i.e., the lowest p-value) is shown. The “Affected patients” column indicates the number of patients with the respective event out of the total number of patients below and above the corresponding dose threshold, respectively. Significant numbers are printed bold

Dose value	Disease-free estimate				Overall survival				Biochemical disease-free estimate
	Thresh. (Gy)	Affected patients (events/total)		p-value	Thresh. (Gy)	Affected patients (events/total)		p-value	Thresh. (Gy)	Affected patients (events/total)		p-value
		Below thresh.	Above thresh.			Below thresh.	Above thresh.			Below thresh.	Above thresh.
D90	108.6	37/263	5/17	0.07	96.9	3/42	59/238	0.020	98.0	5/65	37/215	0.040
D95	100.7	36/258	6/22	0.07	92.3	5/67	57/213	0.002	93.0	6/82	36/198	0.020

Discussion

In this study, we analyzed clinical outcomes of temporary prostate brachytherapy delivered in our center, focusing on the dose-response relationships for urinary toxicity. A key finding of our analysis was the identification of clinically relevant dose thresholds for various OARs, the excess of which was associated with an increased incidence of side effects. Several correlations were found not only for the urethra, but specifically for the EUS and IUS, such as increased dysuria and incontinence when exceeding approximately 102-106 Gy at the EUS. Dose thresholds are equally relevant on the tumor side. However, several limitations must be considered when interpreting these findings. Most importantly, since baseline urinary function was not systematically assessed before treatment, pre-existing urinary symptoms could not be distinguished from treatment-related toxicity. This limits the interpretation of the observed urinary side effects, and may have affected the estimated strength of the reported dose-toxicity associations. Prospective studies incorporating standardized baseline and follow-up assessments of urinary function are therefore warranted to validate the identified dose-response relationships, and to further refine clinically relevant dose thresholds.

While our study focuses especially on toxicity limits, Moll et al. demonstrated that a cumulative EQD₂ ≥ 113 Gy delivered with a brachytherapy boost was associated with improved biochemical control compared with lower boost doses or dose-escalated external beam radiotherapy [26]. Similarly, Trofymov et al. reported superior survival outcomes with higher total doses delivered using intensity-modulated radiotherapy and volumetric modulated arc therapy. Together, these data underline the fundamental dose-response relationship in prostate radiotherapy as well as the importance of therapeutic balance between the effective tumor dose escalation and protection of organs at risk, such as the EUS and IUS [27].

To the best of our knowledge, this is the first systematic analysis of these effects in both HDR and PDR temporary brachytherapy as monotherapy or boost after EBRT; however, similar investigations have been performed previously for permanent LDR prostate brachytherapy using ¹²⁵I seeds. Register et al. reported no correlation between the sphincter dose and incontinence in an examined cohort of 42 patients, with the analysis based on the expanded prostate cancer index composite (EPIC) questionnaire. Their results are in contrast to our findings, which may be explained by methodological differences between both studies. First, Register et al. used MRI-based imaging and included only LDR patients, whereas our cohort was treated based on ultrasound delineations, and was larger and more heterogeneous, especially encompassing all D’Amico risk groups as well as both HDR and PDR treatments [18].

While discrepancies between planned and actual seed positions due to implantation uncertainties or seed displacements are a recognized issue in permanent prostate brachytherapy, in temporary prostate brachytherapy, needle locations are well-known and fixed during treatment, resulting in less dosimetric uncertainties in plan delivery and dose-response analysis [28-30]. Our findings highlight the relevance of considering the EUS and IUS in treatment plan evaluation and adapting, if possible, to the indicated dose constraints, which need to be validated further in investigations by other institutions.

Regarding oncologic outcomes, we observed a 5-year biochemical disease-free estimate (bDFE) of 81% for brachytherapy alone and 85% for brachytherapy boost after EBRT. These results are roughly comparable with those of Martell et al. study, reporting a 5-year bDFE of 91% in a cohort of intermediate-risk patients treated with HDR boost after EBRT, with a slight difference potentially attributed to the higher proportion of high-risk patients (66%) in our study [31]. Similarly, Kittel et al. found a 5-year bDFE of 91.9% and a 10-year bDFE of 81.5% in patients treated with LDR monotherapy across different risk groups [32]. Unlike these studies, our cohort included both HDR and PDR brachytherapy applied as monotherapy or in combination with EBRT, which complicates direct comparisons but reflects broader clinical practice. Additional context is provided by the results of Ishiyama et al., who analyzed 3,424 patients treated with EBRT and HDR boost. Their reported 5- and 10-year bDFE rates (90.6% and 81.4%, respectively) are also comparable with our findings, particularly given a similar risk distribution (67% high- and very high-risk), further supporting the validity of our results [33].

Regarding overall survival, we observed 5-year OS rates of 85% for patients treated with brachytherapy boost after EBRT and 89% for those receiving definitive brachytherapy. These findings are broadly in line with the results reported by Amini et al., who analyzed 10,571 intermediate-risk prostate cancer patients, and found unadjusted 5-year OS rates of 91.4% for EBRT plus brachytherapy vs. 90.2% for brachytherapy alone. The slightly lower survival estimates in our cohort may be partly attributable to the markedly higher proportion of high-risk patients receiving brachytherapy boost included in our study, whereas the referenced analysis was limited to intermediate-risk disease [34]. We observed cumulative local recurrence rates of 2.9% for brachytherapy boost after EBRT and 3.6% for definitive brachytherapy, which closely aligns with Ka et al. findings, who reported a 97% local control rate in 709 patients treated with EBRT and HDR boost [35]. It should be noted that estimates for brachytherapy monotherapy in our cohort are associated with greater uncertainty due to the small patient number.

A consideration of IUS and especially EUS in treatment plan evaluation of temporary prostate brachytherapy may help improving the safety and toxicity profile of respective treatments. Although our findings offer actionable insights for treatment planning and optimization, they are directly connected to the precise delineation of these structures. In this regard, a key aspect of our study is the TRUS-based contouring of urinary sphincters. While MRI allows more precise visualization of these structures, it is still not routinely available for corresponding treatment planning in most clinics. TRUS-based contouring, though inherently less precise, enables practical implementation of respective considerations in routine workflows [36]. By using anatomical landmarks, such as the bladder, prostate, and urethra, our approach to define the urinary sphincters provides a feasible and reproducible method for assessing dose exposure and associated side effects in a real-world setting. Moreover, this highlights the importance of applying unified operational procedures in clinics regarding a suitable organ and target volume delineation, to maintain results comparable and reduce effects of interobserver variabilities on findings of respective dose-response analyses. Under the current circumstances, we are confident that our results in terms of specific dose constraints, can already serve as preliminary guidance but need to be confirmed by multicenter trials. In addition to further dosimetric validation and refined imaging, careful patient selection may represent the next step in optimizing brachytherapy concepts. According to the DEGRO position paper by Spohn et al., genomic classifiers and molecular biomarkers are gaining importance in defining individualized radiotherapy strategies, which could help identifying patients who can benefit the most from intensified treatment approaches [37].

A first fundamental weakness of our analysis is that no baseline data on the initial situation were available, such as the incidence of incontinence, dysuria, or pollakisuria before brachytherapy. Lack of these data limits the significance of our findings regarding the incidence of these side effects after brachytherapy. Furthermore, dose thresholds were identified using a data-driven optimization procedure based on repeated testing of candidate cut-points. Such an approach may overestimate the apparent strength of associations and increase the likelihood of false-positive findings. Therefore, the reported threshold values should be considered exploratory and requiring external validation before clinical implementation. Another limitation of our study is the heterogeneity of the examined patient cohort. Although this reflects the diversity of clinical practice, it complicates statements about the validity of the results for specific sub-groups. This limitation is further intensified by the timing of symptom development, as irritative symptoms are typically most pronounced about one month after completing brachytherapy [38-40]. Part of follow-up examinations was documented later, in some cases not until three months post-treatment, resulting in partial omission of this clinically relevant period in the present analysis. In a prospective study design, a targeted and more frequent gathering of clinical parameters within critical time windows would have been feasible, potentially allowing for a more differentiated and validated assessment of the temporal progression of irritative symptoms.

Dysuria is a subjective symptom and its perception can vary between patients and physicians [41, 42], which can be another drawback of our study. While the LENT/SOMA scale allows standardized grading of dysuric complaints after radiation, the assessment remains largely dependent on patient’s individual pain and discomfort tolerance [21, 43]. This complicates an objective and comparable classification by the investigators. Furthermore, dysuria is an unspecific umbrella term encompassing various forms of voiding dysfunction. A distinction as to whether the symptoms were primarily due to alguria (pain during urination), pollakisuria (increased frequency of urination with small volumes), or other micturition disturbances, cannot be performed retrospectively based on the LENT/SOMA scale. Therefore, the absence of specificity limits the interpretative value of the collected data.

Conclusions

In summary, our exploratory analysis suggests that higher doses to specific anatomical structures, particularly the EUS, may be associated with an increased incidence of urinary toxicity, including dysuria and urinary incontinence. The observed associations indicate that the EUS and potentially also the internal urinary sphincter (IUS), could be relevant structures to consider in future treatment planning and dose-response investigations in prostate brachytherapy. However, the identified dose thresholds should be interpreted with caution given the retrospective study design, the absence of baseline urinary function assessment, and the exploratory threshold-selection procedure.

TRUS-based contouring provides a feasible approach for assessing dose exposure to these structures in routine clinical practice, although further validation using standardized contouring methods and advanced imaging modalities may be beneficial. Prospective multicenter studies with standardized toxicity assessments are warranted to validate the observed dose-response relationships as well as to determine whether robust and clinically applicable dose constraints for the EUS and IUS can be established. Such investigations may help refine treatment planning strategies and further improve the therapeutic ratio of prostate brachytherapy.

Funding

This research received no external funding.

Disclosures

Approval of the Bioethics Committee was not required.

The authors report no conflict of interest.