LONG-TERM RESULTS OF LDR BRACHYTHERAPY FOR LOCALIZED PROSTATE CANCER

Background
Irradiation in LDR-BT is carried out using radioactive isotopes with low radioactivity, e.g. palladium95 or iodine125, which are implanted perineally into the prostate tissue in a short operation and remain there permanently. The advantage of this method lies in the minimally invasive and organ-preserving procedure, with a short inpatient stay or outpatient procedure, low perioperative morbidity and extremely rare postoperative side effects such as incontinence and erectile dysfunction.

Recommendations of the guidelines
The use of LDR-BT as monotherapy for localized low-risk prostate cancer with a Gleason score of 6 (3+3) is recommended by the AWMF S3 guideline. The EAU also recommends LDR-BT for Gleason scores of 7a (3+4). Both guidelines recommend brachytherapy in combination with external percutaneous radiotherapy of the prostate as an alternative treatment for patients with intermediate and high risk [1, 2].

Study situation
LDR-BT has already been investigated retrospectively and prospectively in several studies and showed good oncological results. Table 1 shows an overview of the results of some studies based on biochemical recurrence-free survival (bRFS, i.e. PSA-free survival).

The Seattle Group led by Sylvester et al. published the study with the longest observation period in 2011. 215 patients in the low, intermediate and high risk groups according to D’Amico were examined in the prospective study [3]. With a median follow-up of 15.4 years, the bRFS was 85.9 %; 79.9 % and 62.2 % respectively.

In 2020, the first long-term results on LDR-BT came from German-speaking countries: A Swiss prospective multicenter study by Viktorin-Baier et al. examined 1,291 patients in the low and intermediate risk group treated with LDR-BT. The median follow-up was 37.1 months. After 7 years, the bRFS was 94% for the low-risk group and 83% for intermediate-risk patients. Gleason 7b (4+3) had significantly higher biochemical recurrence rates. Overall, LDR-BT proved to be an effective treatment option for patients with a Gleason score of 6 and 7a [4].

Currently, two completed randomized control trials (RCT) have examined LDR-BT with radical prostatectomy (RP) in terms of oncological effectiveness. For low-risk prostate cancer, the two studies published by Giberti et al. in 2009 and 2017 show no significant difference in the bRFS between the two treatment methods at 91.7-96.1 % (LDR-BT) vs. 91-94.4 % (RP) [5, 6].

An interim report of the ASCENDE-RT study published in 2016 showed significant differences between external beam radiation therapy (EBRT) and LDR-BT in the treatment of intermediate- and high-risk patients. In this RCT, a cohort of 398 men was assigned to an EBRT arm or an EBRT + LDR-BT arm. In the brachytherapy group, the estimated bRFS (according to the Kaplan-Meier method) was between 83-89 % vs. 62-84 % for the EBRT group. Depending on the follow-up, there was a significant difference in the bRFS in favor of the combination of LDR-BT and EBRT. It is noteworthy that there was a significant increase in biochemical recurrences in the EBRT arm after the fourth post-interventional year. After a median follow-up of 6.5 years, the brachytherapy group was twice as likely to be free of biochemical recurrence compared to the EBRT group (HR: 2.04; p = 0.004) [7].

Download Table 1:
Results of other studies of LDR brachytherapy with biochemical recurrence-free survival as an endpoint. Depending on the study with bRFS data of the overall cohort or according to the risk group. *csSP= cancer-specific survival probability.

Side effects and quality of life
The side effects of LDRBT are dominated by irritative micturition problems, which resolve within a year in almost all patients [9]. The ProtecT and PCOS study showed higher rates of incontinence and erectile dysfunction in patients after radical prostatectomy compared to external percutaneous radiotherapy of the prostate [10, 11]. The only randomized control trial that provides data on quality of life after LDR brachytherapy compared to radical prostatectomy is the study conducted by Giberti et al. 2009.

Frequency of use of LDR-BT
Despite good oncological effectiveness with a Gleason score of 6 and 7a, LDR-BT is only used to a limited extent in the treatment of prostate cancer in Germany, compared to radical prostatectomy and external radiotherapy. In the USA, the ratio of radiotherapy to surgical therapy was previously reversed. In the period from 2004 to 2011, around two thirds of all patients in the USA were treated with primary radiotherapy, while one third received a radical prostatectomy. In the same period in Germany, 10% received primary radiotherapy and 66% received RP [13]. More recent data from the USA show a decrease from previously 25 % to 16 % of patients treated with LDR-BT [14]. Reasons for this trend may be the increasing popularity of robot-assisted laparoscopic prostatectomy and the active surveillance firmly anchored in international guidelines. Most recently
the range of indications for active surveillance was extended with the EAU guideline (2022) to include patients with a Gleason score of 7a, which increases the competition for indications [15].
increased [15].

Question
There is a discrepancy in the recommendations between the German and European guidelines regarding the use of LDRBT as a curative treatment option for localized prostate cancer. The recommendation of the German guideline is based on a risk-benefit analysis commissioned by the Federal Joint Committee (G-BA) and published in September 2020. The use of LDR-BT for prostate cancer with a Gleason score of 7a was already controversially discussed there [16]. The study by Viktorin-Baier et al., which showed almost identical efficacy in patients with a Gleason score of 6 or 7a, prompted us to examine these results in a German cohort.

Download Table 2:
Patient characteristics and hazard ratios of biochemical recurrence-free survival (bRFS).

Study design & research methods
In our multicenter retrospective study, we examined 733 patients with localized prostate cancer treated with LDR-BT in the period from 2004-2019. The procedures were performed at the Clinic for Urology and Pediatric Urology at the SLK Clinics in Heilbronn and the urology department of the Emmendingen District Hospital with identical radiation technology and seed activity. Age, Gleason score, initial prostate-specific antigen value (iPSA), total and positive prostate punch biopsies, prostate side involvement, prostate volume and PSA history values were among the parameters recorded. The PSA values were evaluated during the follow-up of patients three, six and twelve months after implantation and then annually. Patients with at least six months of follow-up were included in the study. The “nadir+2 ng/ml” definition (Phoenix definition) was used to define a biochemical recurrence. The bRFS was evaluated as the primary endpoint. The cohort was stratified according to the parameters listed in ▶ Table 2 and individual factors influencing the bRFS were examined. The bRFS of the subgroups was calculated for the parameters with a significant influence (p-value < 0.05) using the Kaplan-Meier method. Furthermore, multivariate and univariate regression analyses as well as the calculation of hazard ratios (HR) according to Cox regression models were performed. Irradiation technology
The radioactive isotope iodine125 served as the radiation source. The iodine125 contained in seeds was implanted transperineally into the prostate using the “4D method” with hollow needles. The 4D method results from
the 3D planning of the target volume (i.e. prostate) and the placement of the seeds under “real-time conditions”. The 3D planning was initially performed using transrectal ultrasound (TRUS) of the prostate to determine the target volume.
the target volume. This was followed by template and TRUS-guided implantation. Using the 4D method, the localization of the needle could be localized by the TRUS image in the planning system before the seeds were placed and the planned position could be compared with the actual position (▶ Fig. 1).

Fig. 1:
a) Schematic procedure for the volume study of the prostate in 5 mm slices
b) Drawing of the target and risk organs using planning software
c) Template- and TRUS-guided seed implantation in lithotomy position
d) Satisfactory result with orthotopically inserted and homogeneously distributed seeds