Comparison of post-implant dosimetrics between intraoperatively built custom-linked seeds and loose seeds by sector analysis at 24 hours and 1 month for localized prostate cancer

Purpose

Prostate cancer is one of the most common malignancies in men and is a major cause of cancer death [1]. Prostate-specific antigen (PSA) screening enables the detection of early and localized prostate cancer. There are many therapeutic options for patients with localized prostate cancer, including androgen deprivation therapy (ADT), radical prostatectomy, external beam radiation therapy, and brachytherapy. Permanent seed brachytherapy, also termed low-dose-rate (LDR) brachytherapy, enables a high-dose of radiation to the prostate, with a steep dose gradient to the surrounding normal tissues. Previous reviews have shown that outcomes of brachytherapy for localized prostate cancer are comparable to those of other therapeutic modalities, including radical prostatectomy and external beam radiation therapy [2,3,4].

Zauls et al. first reported intraoperatively built custom-linked (IBCL) seeds, as a push-button delivery system that uses a combination of seeds, connectors, and spacers [5]. LDR brachytherapy was first adopted in 2003 in Japan, but stranded or linked seeds were not introduced until 2012, and only loose seeds (LS) had been used for LDR brachytherapy until then [6]. Several studies have reported the advantages and disadvantages of IBCL seeds compared with LS [5,7,8,9,10,11,12,13]. IBCL seeds have the advantages of less migration, and stability due to intraoperative linking, indicating the benefits of loose and stranded seeds [14]. Therefore, we hypothesized that compared with LS, the use of IBCL seeds might reduce variance in the dosimetric parameters. To the best of our knowledge, no previous report has evaluated the variability in dosimetric parameters in a comparison of IBCL seeds and LS.

Moreover, the optimal timing for obtaining post-implant computed tomography (CT) and/or magnetic resonance (MR) imaging remains a debated issue. Because prostatic edema arises in the first 24 hours after implantation, post-implant imaging obtained within 24 hours results in lower calculated doses [15,16]. Some studies suggest an interval of 2 to 6 weeks after implantation, when prostatic edema has decreased [17,18]; whereas others have recommended dosimetric evaluation within 24 hours, because this allows for immediate correction of a possible dose deficiency [19,20,21]. In addition, although most previous reports refer to the dosimetric parameters of the whole prostate, some have evaluated dose distribution in different regions of the prostate [10]. We have previously reported the usefulness of sector analysis for localized prostate cancer treated with LS [22].

The purpose of this study was to compare the dose distribution and to evaluate the variation in dosimetric parameters between IBCL seeds and LS, using sector analysis at 24 hours and 1 month after brachytherapy.

Material and methods

Post-implant dosimetry

Post-implant axial CT images of the pelvis were obtained 24 hours and 1 month (median, 29 days) after the implant procedure, using an Asteion (Toshiba Medical Systems, Tokyo, Japan) at 2.0 mm thickness with the patient in the supine position. Post-implant dosimetric analysis was re-planned with the Oncentra TPS by a single radiation oncologist (E.O.). CT-MR image fusion for delineation was performed for all patients with the Oncentra TPS, using the MR images obtained in the pre-implant volume studies. The percentage changes in the volumetric parameters after 24 hours and 1 month were defined as follows:

Δvariable (%)=(variable1month−variable24h)/variable24h×100

Homogeneity index (HI) was defined as follows [24]:

HI(%)=(PV100−PV150)/PV100×100

The prostate volume was divided into four quadrants, such as anterior-superior quadrant (ASQ), posterior-superior quadrant (PSQ), anterior-inferior quadrant (AIQ), and posterior-inferior quadrant (PIQ). The superior- inferior and anterior-posterior segments were divided by the midpoint of the prostate on reconstructed CT images (Figure 1) [22].

Fig. 1

Division of the prostate into four quadrants

ASQ – anterior-superior quadrant, PSQ – posterior-superior quadrant, AIQ – anterior-inferior quadrant, PIQ – posterior-inferior quadrant

Seed migration was defined as the presence of one or more seeds ≥ 2 cm outside the prostate contour on a post-implant pelvic CT or X-ray. Seed loss was defined as unintentional reduction of seed number at the post-implant evaluation, excluding migrated seeds.

Results

Table 1 lists the patient characteristics. The median follow-up time was 49.9 months in the LS group and 27.1 months in the IBCL group (p < 0.001). Fourteen patients received neoadjuvant ADT 3-6 months before brachytherapy (luteinizing hormone-releasing hormone agonist, n = 10; maximum androgen blockade [combination of luteinizing hormone-releasing hormone agonist and anti-androgen], n = 2; anti-androgen, n = 2). No biochemical recurrence occurred during the follow-up period, and one patient died of lung cancer.

Analysis of adverse events

No grade 3 or higher GU or GI adverse events were observed. Two patients (6.3%) in each group experienced at least one episode of hematuria. Two patients (6.3%) in the LS group and 1 patient (3.1%) in the IBCL group experienced rectal hemorrhage. Figure 2 shows the frequency of grade 2 GU adverse events between 3 and 12 months after brachytherapy. At 3 months after treatment, the frequency of GU adverse events was significantly lower in the IBCL group (p = 0.032), and there was no significant difference in the other periods. Using UV₁₅₀ and UD₃₀ at 1 month, ROC analysis was performed for the frequency of GU adverse events after 3 months. The respective cut-off values for UV₁₅₀ and UD₃₀ at 1 month were 43.5% (AUC = 0.70, sensitivity = 66.7%, specificity = 74.4%) and 162.1% (AUC = 0.71, sensitivity = 66.7%, specificity = 76.7%). Figure 3 shows the change in the frequency of grade 2 GU adverse events using the cut-off value of UV₁₅₀; significant differences at 3, 6, and 9 months (p < 0.001, 0.019, and 0.044, respectively) were noted.

Fig. 2

Incidence of grade 2 or higher GU adverse events between 3 months and 1 year after brachytherapy in the LS and IBCL groups

^*Statistically significant difference between the two groups, LS – loose seed, IBCL – intraoperatively built custom-linked, GU – genitourinary

Fig. 3

Incidence of grade 2 or higher GU adverse events between 3 months and 1 year after brachytherapy, based on a cut-off value of UV150

^*Statistically significant difference between the two groups, UV150 – urethral V150 (the percentage of the volume receiving 150% of the prescribed dose), GU – genitourinary

Discussion

The results of this study show that compared with LS, the SD of most dosimetric variables was lower for IBCL seeds, and statistically significant differences between the two groups were found for several variables (F-test; PV₁₅₀, UV₁₅₀, and UD₃₀ at 24 hours, and UD₃₀ at 1 month). Although sector analysis of V₁₅₀ and D₉₀ showed a general decrease in the SD for all sectors in the IBCL group, no statistically significant difference was observed. Analysis of changes in the variables showed a significant or near-significant decrease in SD; in sector analysis, the SD of changes in D₉₀ in the IBCL group was also significantly lower compared with the LS group. These results indicate that compared with LS, the use of IBCL seeds can reduce variance of the dosimetric parameters. More importantly, the reduction in variance due to the use of IBCL seeds was more pronounced in the analysis of changes between 24 hours and 1 month, which indicates that compared with LS, using IBCL seeds improves the accuracy of predicting dosimetric parameters at 1 month, using those obtained at 24 hours. Furthermore, this result may ensure the validity of early dose correction, when dose deficiency is recognized as early as 24 hours after brachytherapy, when IBCL seeds are used.

The use of IBCL seeds also makes it possible to reduce high-dose areas in the prostate, improve HI, and reduce urethral dose for the whole prostate as well as each sector. PV₁₀₀ and PD₉₀ were not significantly different between the two groups. Many studies have compared dosimetric parameters between these groups, but the results are controversial (Table 4). Several papers have reported no significant difference in PV₁₀₀ and PD₉₀ between the two groups [5,8,10]. Inada et al. reported that PV₁₀₀ was significantly higher in the IBCL group than in the LS group, whereas other studies showed that PD₉₀ was significantly lower in the IBCL group than in the LS group [7,11,12,13]. In several studies, PV₁₅₀ and UD₃₀ were significantly lower and HI was significantly higher in the IBCL group than in the LS group, consistent with the results of the present study [7,11]. Two studies have reported that RV₁₀₀ was significantly lower in the IBCL group than in the LS group, but we found no significant difference in the present study [7,13]. We consider that the decrease in variation of dosimetric parameters and the reduction of high-dose areas in both the prostate and urethra are due to the following characteristics of IBCL seeds compared with LS: (i) reduction of seed migration and loss, (ii) suppression of unintentional movement within the prostate after seed implantation, (iii) correct distance between seeds due to use of spacers, and (iv) the ability to intentionally place the seeds outside the prostate, which is particularly useful in peripheral loading techniques, and contributes to reducing urethral dose.

In the sector analysis, although there were no significantly lower sectors in D₉₀ at 24 hours in the IBCL group, D₉₀ of PIQ at 24 hours in the LS group was significantly lower compared with the other sectors. However, there was no significant difference between the two groups in D₉₀ at 1 month. This may be because LS can change position according to edema of the prostate after seed implantation, and return to the intended position after resolution of the edema; whereas with IBCL seeds, the seeds are less able to move even if edema is present. In their comparison between IBCL seeds and LS, Katayama et al. performed sector analysis and reported improved dose distribution in the anterior base in the IBCL group [10]. Although our method of segmentation is different to theirs, there was no significant difference in the present study between the two groups in terms of D₉₀ and V₁₀₀ of AIQ at 24 hours or at 1 month.

The prevalence of GU adverse events at 3 months after implantation was significantly lower in the IBCL group than in the LS group. Furthermore, in the comparison using a cut-off value of UD₁₅₀, the incidence of GU adverse events was significantly lower in patients with lower UD₁₅₀. These results suggest that high urethral dose is associated with the occurrence of GU adverse events and that fewer GU adverse events occur in the IBCL group because the dose to the urethra was lower in this group. In their studies regarding GU adverse events after brachytherapy, Ishiyama et al. and Katayama et al. found no significant difference in the prevalence of adverse events between the two groups [8,10]. These previous studies evaluated only the presence or absence of adverse events, whereas the present study examined the frequency of adverse events according to the length of follow-up period, which we consider to be a more detailed analysis and the first to show a statistical advantage of IBCL seeds over LS in terms of GU adverse effects. Even though the optimal prescription dose in LDR brachytherapy is controversial, numerous studies have reported a correlation of PD₉₀ and PV₁₀₀ with prognosis [26,27,28,29,30]. As mentioned above, the present study found no significant difference in PD₉₀ and PV₁₀₀ between the IBCL and LS groups. Thus, these results suggest that IBCL seeds can reduce urethral dose without lowering PD₉₀ and PV₁₀₀. Moreover, the use of IBCL seeds may enable the prescription dose to increase without increasing GU adverse events and reduce biochemical recurrence of prostate cancer. These results suggest that IBCL seeds are especially recommended for small prostates. When the prostate is small, there is a limited space within the prostate, in which seeds can be inserted, and reducing the urethral dose is often difficult. Other situations where IBCL seeds may be recommended include combination therapy of brachytherapy and external beam radiation therapy, which also requires reduction of urethral dose.

This study had several limitations. First, it was limited by its retrospective design and single-center setting, a relatively short follow-up period, and a relatively low number of patients. The median follow-up time of 4.2 years in the LS group is considered short for assessing the prognosis of localized prostate cancer. However, no biological recurrence was observed during this follow-up period, and the therapeutic results of both groups may be considered acceptable. Second, CT images were used for dose evaluation. It is well-known that the seeds cause artifacts on CT that make it difficult to contour the margin of the prostate, and that contouring of the prostate varies greatly between practitioners [31,32,33]. To eliminate these effects, we used CT-MR fusion images for contouring. Third, the brachytherapy methods vary greatly among facilities, such as prescription doses, dose limitations for organ at risk, seed insertion techniques, and evaluation periods. Therefore, attention should be given when applying the results of this study to other facilities.

Conclusions

In this retrospective single institutional study, as compared with the LS group, the IBCL group showed a decrease in the SD of the dosimetric parameters, which were statistically significant with respect to change in the variables between 24 hours and 1 month (F-test). The use of IBCL seeds significantly decreased PV₁₅₀, UV₁₅₀, and UD₃₀, and significantly improved HI without lowering PD₉₀ and PD₁₀₀. The prevalence of GU adverse events at 3 months was significantly lower in the IBCL group than in the LS group.