Plan reproducibility of intraoperatively custom-built linked seeds compared to loose seeds for prostate brachytherapy.

PURPOSE: Few studies have compared the implant quality of linked and loose seeds for prostate brachytherapy. This study aimed to evaluate and compare plan reproducibility of intraoperatively built custom linked seeds and loose seeds for prostate brachytherapy.
MATERIAL AND METHODS: Between December 2010 and March 2014, 76 localized prostate cancer patients received Iodine-125 brachytherapy with external beam radiotherapy. Linked and loose seeds were implanted in 39 and 37 patients, respectively. The primary endpoint was the mean (± standard deviation) of the absolute change in the minimum dose received by 90% of the prostate volume between intraoperative and post-operative planning (ΔD90) to confirm plan reproducibility. Comparisons between the groups were evaluated using 2-sample t tests.
RESULTS: The ΔD90 values were 6.95 ± 11.6% and -0.41 ± 8.5% for the loose and linked seed groups, respectively (p < 0.01). The linked seed group showed decreased post-operative D90 (118.8% vs. 127.2%), V150 (51.7% vs. 66.7%), and RV100 (0.44 ml vs. 0.61 ml) compared to the loose seed group (p < 0.01), whereas lung migration tended to be reduced (0% vs. 8%).
CONCLUSIONS: The plan reproducibility of the linked seed group was better than that of the loose seed group. Moreover, the linked seed group showed less migration and lower rectal dose.

Purpose

Permanent prostate brachytherapy is a standard treatment option for localized prostate cancer. In Japan, this treatment has been performed since 2003 and has recently gained popularity. Recent evidence has demonstrated an excellent biochemical control rate for patients treated with brachytherapy alone or in combination with external radiation [1,2,3,4,5,6]. Low-dose-rate prostate brachytherapy techniques have several variations, including loose vs. stranded seeds and preplan vs. intraoperative techniques. Until 2012, when stranded or linked seeds were first introduced, the most popular approach in Japan was the intraoperative technique using loose seeds [7,8]. However, problems with loose seeds include migration to distant sites (e.g., the lungs) [9,10,11,12] and possible deterioration of dosimetry due to this migration [10,11,13,14,15,16]. Zauls et al. [17] first reported the outline for the technique of linked seeds. With this approach, the user can create intraoperatively built custom linked seeds, using a combination of seeds, connectors, and spacers. The advantages of linked seeds include intraoperative customization, less migration, and increased stabilization due to linking, indicating the benefits of loose plus stranded seeds [18].

To date, many studies compared stranded seeds to loose seeds [9,13,14,19,20,21], but few studies have compared the implant quality of linked seeds with that of loose seeds for prostate brachytherapy [17,22,23,24,25]; however, until now, there have been no reports about the plan reproducibility of linked seeds. Generally, intraoperative dosimetry based on ultrasound would not predict biochemical outcome [26]. Post-operative D90 is an important dosimetric parameter for biochemical freedom from failure [27]. A recent report revealed that intraoperative magnetic resonance imaging/ultrasound fusion may improve prostate dosimetry [28] but post-operative computed tomography (CT)-based dosimetry remains the gold standard for the evaluation of implant quality. Therefore, the reproducibility of both intraoperative and post-operative planning is important for implant evaluation. We hypothesized that the plan reproducibility of linked seeds between intraoperative planning and post-operative planning would be good, on the assumption that linked seeds are connected to each other and do not move easily after seed placement. In the present study, to address this hypothesis, we focused on the post-operative minimum dose received by 90% of the prostate volume (D90). If the absolute change in prostate D90 (ΔD90 = post-operative D90 – intraoperative D90) is low, the plan reproducibility is considered to be high. To date, no studies on dosimetric reproducibility of linked seeds have been reported. Therefore, our study, which further investigated the usefulness of linked seeds, provides novel information on this issue.

The primary endpoint of our analysis was the mean (± standard deviation) of the ΔD90 as a means to confirm plan reproducibility. The secondary endpoints were the comparisons of other dosimetric parameters as well as seed migration between linked and loose seeds for prostate brachytherapy.

Material and methods

Between December 2010 and March 2014, 76 patients with localized prostate cancer receiving Iodine-125 brachytherapy combined with external beam radiation therapy (EBRT) at the National Hospital Organization Saitama Hospital were analyzed. The following risk factors related to prostate cancer were assessed: serum levels of prostate specific antigen (PSA), Gleason score, and TNM stage. The subjects were divided into low-risk (T1-2a: PSA < 10 ng/ml and Gleason score ≤ 6), intermediate-risk (T2b: PSA 10-20 ng/ml, or Gleason score = 7), and high-risk (T2c-3: PSA > 20 ng/ml, or Gleason score ≥ 8) groups. The intermediate to high-risk group patients, and the low-risk group patients with positive core needle biopsy rates > 33% received combined therapy. This retrospective study was approved by the institutional review board.

All patients underwent an ultrasonography volume study one month before implantation to determine the number of seeds needed. Loose seeds (Brachysource; CR Bard, Covington, GA, USA) were implanted in 37 patients using a Mick applicator (Mick Radio-Nuclear Instruments, Inc., Bronx, NY, USA). The mean activity per seed was 0.35 U (range, 0.29-0.46 U), and total seed activity was 19.2 U (range, 11.2-27.1 U). Linked seeds (Brachysource; CR Bard, Covington, GA, USA) were implanted in 39 patients using a Quicklink device (CR Bard, Covington, GA, USA). The mean activity per seed was 0.32 U (range, 0.27-0.38 U), and total seed activity was 18.8 U (range, 13.3-27.5 U). A medical physicist checked the intensity of Iodine-125 seed sources. Implantation was carried out using an interactive transrectal ultrasound (SSD-3500 SV; Hitachi Aloka Medical Co., Ltd.)-guided technique with a modified peripheral loading pattern by using the VariSeed 8.0 planning system (Varian Medical Systems, Inc., Palo Alto, CA, USA) [29].

The prostate, urethra, and rectal wall were contoured by a radiation oncologist. The planned target volume was defined as the entire prostate. Urethra was visualized on ultrasound images using a catheter. The width of the urethral catheter was 18 F in diameter. The prescribed dose to the planned target volume was 110 Gy for intraoperative planning. Supplemental EBRT was started one month after implantation. All patients received a median dose of 45 Gy (range, 30.6-50.4 Gy) at 1.8 Gy per fraction, using 10-MV photons delivered by a three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) with a linear accelerator (ONCOR Impression Plus; Siemens Medical Solutions, Erlangen, Germany). The prescribed EBRT dose varied according to the dosimetric findings at the time of the post-implant dosimetry.

Computed tomography of the prostate was obtained one month post-operatively in the supine position, with 20 slice detector arrays (SOMATOM Sensation Open; Siemens Medical Solutions, Erlangen, Germany). Axial computed tomography images of the pelvic area were taken at a 3-mm thickness and 3-mm intervals. The post-implant planning for dosimetric assumption in clinical dosimetry was done using the VariSeed 8.0 planning system (Varian Medical Systems, Inc., Palo Alto, CA, USA). The entire prostate, excluding the seminal vesicles, was contoured from the base to the apex. As urinary catheters were not used for the post-implant dosimetry, it was not possible to identify the urethral position. We modified the post-implant urethral position with the help of their intraoperative ultrasound findings. The rectum was contoured as a solid structure defined by the outer wall on all slices showing seeds, without attempting to differentiate the inner wall or the contents. A frontal chest plain radiograph was obtained two weeks post-operatively to check for seed migration to the lungs. The calculated dosimetric parameters included the percent volume of the post-implant prostate receiving 100% and 150% of the prescribed dose (V100 and V150, respectively), and the D90. The ΔD90 was also evaluated. To analyze the entire cohort (n = 76), the delivered doses were converted to percentages of the prescribed dose. In addition, the rectal dose was expressed as the rectal volume receiving > 100% of the prescribed dose (RV100), and as the minimum dose received by the hottest 2 cc of the rectum, as recommended by the AAPM Task Group 137 [30].

The quantitative variables are described as arithmetic means and standard deviations. The normality of the sample has been confirmed statistically. The 2-sample t test was used for comparing the two groups. All tests and confidence intervals were two-sided, and a value of p ≤ 0.05 was considered to indicate statistical significance. Analyses were carried out using SPSS version 22.0 (SPSS Inc., Chicago, IL, USA).

Results

The clinical characteristics of the 76 patients are shown in Table 1. Table 2 shows the dosimetric results of the intraoperative plan. The same predetermined dosimetric parameters for prostate (110 Gy) were used in both groups, and no dose escalation for the prostate was intended for the linked seed group. Significant differences in the V150 and seed activity were seen between the groups. Table 3 shows the dosimetric results of the computed tomography analysis from one month post-operatively. The D90, V150, RV100, and ΔD90 in the linked seed group were significantly lower compared with those in the loose seed group. Figure 1 presents a histogram of the ΔD90 values in the loose and linked seed groups. The ΔD90 in the linked seed group showed a lower mean value and narrower distribution (–0.41 ± 8.5%) than the loose seed group (6.95 ± 11.6%) (p < 0.01). Migration to the lungs was not seen in any patients in the linked seed group (0%), as compared to 3 patients (1-4 seeds per patient) in the loose seed group (8%; p = 0.070).

Table 1

Clinical characteristics

Factor	Loose seed group	Linked seed group	p
n	37	39
Age (years)
Median (range)	73 (62-79)	71 (52-79)	0.090
Risk category			0.27
Low	6 (16%)	3 (8%)
Intermediate	26 (70%)	26 (67%)
High	5 (14%)	10 (26%)
Hormonal therapy	11 (30%)	19 (49%)	0.090

Unless otherwise specified, the values are given as numbers

Table 2

Intraoperative parameters

Factor	Loose seed group	Linked seed group	p
Prostate volume (ml)	21.2 (5.8)	21.2 (7.3)	0.95
Implanted seed number	55.3 (8.6)	59.3 (9.4)	0.060
Seed activity (U)	0.35 (0.032)	0.32 (0.026)	< 0.001
Total seed activity (U)	19.2 (3.7)	18.8 (4.0)	0.67
D90 (%)	120.3 (5.1)	119.2 (5.5)	0.40
V100 (%)	98.4 (1.4)	98.8 (1.1)	0.14
V150 (%)	47.7 (6.4)	43.0 (7.5)	< 0.01

Values are given as the mean (± standard deviation).

D90 – the minimum dose received by 90% of the prostate volume; V100 – the percent volume of the prostate receiving 100% of the prescribed dose; V150 – the percent volume of the prostate receiving 150% of the prescribed dose

Table 3

Post-operative parameters

Factor	Loose seed group	Linked seed group	p
Prostate volume (ml)	22.1 (5.9)	23.5 (7.4)	0.37
D90 (%)	127.2 (11.4)	118.8 (9.2)	< 0.01
V100 (%)	98.7 (1.4)	98.0 (1.9)	0.06
V150 (%)	66.7 (13.2)	51.7 (11.4)	< 0.001
ΔD90 (%)	6.95 (11.6)	–0.41 (8.5)	< 0.01
RV100 (ml)	0.61 (0.35)	0.44 (0.27)	0.03
RD2cc (%)	68.1 (12.3)	64.6 (10.4)	0.18

Values are given as the mean (± standard deviation).

D90 – the minimum dose received by 90% of the prostate volume; V100 – the percent volume of the prostate receiving 100% of the prescribed dose; V150 – the percent volume of the prostate receiving 150% of the prescribed dose; ΔD90 – the postoperative D90 minus intraoperative D90; RV100 – the rectal volume receiving > 100% of the prescribed dose; RD2cc – the minimum dose received by 2 cc of the rectum

Fig. 1

Histogram of the difference in the minimum dose received by 90% of the prostate volume (ΔD90) in the loose and linked seed groups

Discussion

Our study revealed the dosimetric advantages, including less seed migration, of linked seeds compared to loose seeds. The mean of the ΔD90 significantly decreased towards zero and the standard deviation of the ΔD90 was narrow in the linked seed group (–0.41 ± 8.5%) compared with that in the loose seed group (6.95 ± 11.6%), which showed almost identical intraoperative and post-operative D90 values. Since linked seeds are connected to each other, the seeds do not move easily in the prostate after implantation. Therefore, the dose distribution of the intraoperative D90 is stable up to post-operative planning. That is, intraoperative planning can be reproduced in the post-operative planning. In previous reports [17,24], the ΔD90 showed no statistically significant difference between linked and loose seeds, unlike in our study. In our study, the prostate D90 of the intraoperative plan was almost the same as that of the post-operative plan in the linked seed group. Hence, we can achieve a reliable plan in the intraoperative phase. Our study is distinct from previous studies because we focus on dosimetric reproducibility of linked seeds using ΔD90 as an indicator. Therefore, it newly shows that intraoperative custom-built linked seeds are valuable in prostate brachytherapy.

In the present study, the post-operative prostate D90, V150, and RV100 decreased in the linked seed group compared with that in the loose seed group. However, although the post-operative D90 decreased in the linked seed group compared to the loose seed group, the prescription dose was maintained (D90 > 100%). Thus, as the irradiation dose of the prostate is maintained, this difference may have little clinical impact. Further, reduction of the post-operative V150 leads to a reduction over the high-dose region of the prostate. As the rectal dose also shows downward trends, a reduction of adverse events can be expected as a result. Placing linked seeds on or adjacent to the prostate capsule can cover a dose from the extracapsular area. Since linked seeds are more spaced apart, the seed-to-seed distance is greater in the prostate compared with loose seeds; therefore, the high-dose region (V150) in the prostate may be reduced. Additionally, as linked seeds can be customized intraoperatively compared with suture-embedded seeds, the high-dose regions of the rectum may also be reduced.

Table 4 shows the previous studies comparing the dose parameters between linked and loose seeds. Regarding the D90 and the rectal dose for the linked seed group, five previous reports showed no significant differences, while one report showed significantly lower doses in the linked seed group.

Table 4

Literature survey of dosimetric comparisons between linked and loose seeds

Study [ref]	n (linked/loose)*	Parameter	Linked seeds	Loose seeds	p
Zauls et al. [17]	91 (48/43)	D90	165.1%	164.5%	NS
		ΔD90	–8.3%	–5.5%	NS
		% of RV100 > 1.3 cc	27.6%	16.7%	NS
Jarusevicius et al. [22]	230 (124/106)	D90	177.9 Gy	184.7 Gy	0.002
		V100	94.9%	95.5%	NS
		V150	53.2%	65.3%	< 0.001
		RV100	0.3 ml	0.6 ml	< 0.001
Ishiyama et al. [31]	140 (74/66)	D90	174.4 Gy	170.7 Gy	NS
		V100	96.60%	95.70%	NS
		V150	60.40%	62.10%	NS
		RV100	0.47 ml	0.51 ml	NS
Ishiyama et al. [24]	630 (314/316)	D90	118.1%	119.3%	NS
		ΔD90	–3.82%	–3.14%	NS
		V100	95.5%	95.5%	NS
		V150	60.2%	67.6%	< 0.001
Katayama et al. [23]	64 (32/32)	D90	180.7 Gy	178.1 Gy	NS
		V100	98.2%	97.0%	NS
		RV100	0.97 ml	1.00 ml	NS
Inada et al. [25]	74 (37/37)	D90	119.8%	115.5%	NS
		V100	96.9%	95.2%	0.02
		V150	57.1%	64.5%	0.005
		RD2cc	61.0%	64.1%	NS
Present study	76 (39/37)	D90	118.8%	127.2%	< 0.01
		ΔD90	–0.41%	6.95%	< 0.01
		V100	98.0%	98.7%	0.061
		V150	51.7%	66.7%	< 0.001
		RV100	0.44 ml	0.61 ml	0.030

Values are presented as the means based on the one-month computed tomography analyses. Bold figures represent significantly higher values.

The number of patients in linked/loose seed group was indicated in parentheses.

NS – not significant, D90 – the minimum dose received by 90% of the prostate volume, V100 – the percent volume of the prostate receiving 100% of the prescribed dose, V150 – the percent volume of the prostate receiving 150% of the prescribed dose, ΔD90 – the post-operative D90 minus intraoperative D90, RV100 – the rectal volume receiving > 100% of the prescribed dose, RD2cc – the minimum dose received by 2 cc of the rectum

Lastly, our study showed no significant difference in migration between the two groups, although a declining trend was noted in the linked seed group. We hypothesize that this finding is due to the fact that it may be difficult for the seeds to migrate out of the prostate because each linked seed is connected. Accordingly, previous studies have also shown significant reductions in the seed migration rate. Tapen et al. reported lower lung migration for stranded seeds compared to loose seeds (0.7% vs. 11%, p = 0.002) [12], and Ishiyama et al. reported lower migration in linked compared to loose seeds (0% vs. 52%, p < 0.001), and lower lung migration (0% vs. 30%) [31]. However, the impact on the dose distribution by migration is debatable. Wang et al. [32] reported that the prostate post-implant V100, D90, and rectal wall RV100 for patients without seed loss were 94.6%, 113.9%, and 0.98 cm3, respectively, as compared to 95.0%, 114.8%, and 0.95 cm3 for the group with seed loss; there were no correlations between seed loss due to migration and post-plan dosimetry. Miyazawa et al. reported that the D90 was 150.0 ± 19.6 Gy in patients without seed migration and 149.5 ± 19.4 Gy in patients with seed migration, and also found no significant difference in the post-planning dose delivered to the prostate between patients that did and did not display seed migration [33]. Of note, there are several reports on adverse events due to seed migration. Several studies have reported radiation pneumonitis, acute myocardial infarction, and secondary carcinoma due to migration [34,35,36]. Reducing migration using linked seeds may decrease these concerns.

Our study has some limitations. Most importantly, this study was a retrospective analysis, and further prospective studies are needed to confirm our findings. As urinary catheters were not used for the post-implant dosimetry, there were uncertainties of urethral delineation and dosimetry. Therefore, we did not evaluate the urethral dose for post-operative planning. However, because all patients were treated by the same radiation oncologist and urologist, inter-observer variability in dosimetry should be limited in our study.

Conclusions

Linked seeds showed reduced differences in terms of the prostate D90 between intraoperative and post-operative planning compared to loose seeds. Thus, the post-operative plan was reproduced intraoperatively. In addition, the high-dose region in the prostate, and the rectal dose was decreased using linked seeds, as was the lung migration.