Intra-prostatic gold fiducial marker insertion for image-guided radiotherapy (IGRT): five-year experience on 795 patients

Prostate cancer is the second most commonly diagnosed cancer in males [1]. According to patient preferences and life expectancy, treatment options include active surveillance, radical prostatectomy, or radiotherapy (external beam radiation therapy [EBRT] or brachytherapy [2, 3]. Regarding EBRT, daily gland displacement could lead to a target missing secondary to significant prostate motion during radiotherapy [4]. Therefore, prostate motions must be considered to set the target margins for radiotherapy [5]. Fiducial markers (FMs) can facilitate the tracking of inter- or intrafraction prostate motions, thereby, image-guided radiotherapy (IGRT). Hence, radiotherapy with FMs benefits from reduced target margins [6]. Besides, FMs can be applied for daily prostate position verification and correction before and during IGRT [7]. The accuracy, safety, low cost, and reproducibility of FM have made it the most acceptable approach to tracking prostate motions during radiotherapy [8]. The hydrogel spacer method is another way to reduce the radiation that reaches the organ at risk (OAR). Pepe et al. found that using a hydrogel spacer before hypofractionated prostate cancer radiotherapy helps to reduce the genitourinary and rectal toxicities [9].

There are two main approaches for FM insertion: transrectal and transperineal, both usually under trans-rectal ultrasound (TRUS) guidance. Both approaches are safe and well tolerated [10‐13]. The transperineal approach has a lower risk of infection rates. Nevertheless, this difference is minimal (0.5%) [14]. On the other hand, the transperineal fiducial marker implantation may lead to more risk of bleeding and pain [15]. Overall, both approaches are acceptable in nowadays practice, and using transrectal or transperineal approach are mainly based on radiologist preference. Several studies reported low or moderate rates of complications following FM [11, 12, 16, 17]. However, controversies also exist regarding complication rates; Loh et al. realized that the adverse effects of FM implantation are underestimated [15].

The efficacy of FMs for prostate IGRT is based on the assumption that each marker will remain fixed in position during planning and treatment. FM migration can occur; however, the migration rate and its importance in clinical practice, which could lead to significant limitations to utilizing FMs for prostate radiotherapy, should be assessed. Also, developing a standardized protocol for FM insertion to minimize known complications and migration should be considered.

In the current study, we present our five-year experiences of TR insertion of intra-prostatic gold FM in 795 patients with prostate cancer candidates for IGRT. The detailed procedure and rates of complication and migration are outlined. To the authors’ knowledge, this is the largest series of intra-prostatic FM insertion. In addition, this is one of the published reports of FM insertion in patients after radical prostatectomy. The results of this study can provide a basis for future studies on the application of intraprostatic FM for advanced radiotherapy techniques.

Advanced radiotherapy techniques, such as IMRT, can lead to superior precision and optimization of the treatments associated with reduced doses to the OAR, thereby toxicities. This benefit can help to escalate the dose to the target tissue and improves the disease control. The major problem in IMRT of prostate cancer is the considerable prostate motion. It has been demonstrated that the prostate can displace even 18 mm during a radiotherapy session [20]. This issue would increase the target volume and lead the protecting the OAR (including rectum and bladder) into trouble [21]. This problem can be minimized by tracking the prostate motion, developed in IGRT systems [22]. To this end, one of the most common approaches is FM tracking during radiotherapy sessions.

Evidence supports the FM insertion to track prostate motion during the radiotherapy course. It can assist to improve the biochemical tumor control [23] and reducing the toxicities [24, 25]. However, the available information on its success rate and complications is not in concert. Moman et al. reported one of the largest published series about the practical feasibility, success, and complication of intraprostatic FMs. They found a success rate of 99% and complications rate of 3.9%. The most common reported complication was hematuria (1%) [14]. Igdem et al. prospectively quantified patient-reported morbidity of TRUS-guided TR implantation of three gold FMs in 135 respondents. No anesthesia was applied. Five patients reported rectal bleeding and 20 patients experienced hematuria. No case required additional therapeutic intervention. Three patients experienced urinary infection requiring additional antibiotics [11]. In another study by Kably et al. on 75 patients, the success and complication rates were 99% and 10.6%, respectively. The most common complication was intraprostatic hemorrhage (4%) [16]. Our study reports the same endpoints in 795 patients, which constitute one of the largest series. In this cohort, the success rate was higher (99.8%), and the complication rate was lower (2.6%). Grade 3–4 complications was not detected and the reported complications (2.6%) were mild sepsis or urinary retention. Lower complications may reside in our technique. Applying needles with a narrower lumen compared to the Kably et al. (gauge 18 vs. 17) may justify the lower rates of urinary retention (1.6% vs. 11.4%) and perirectal hemorrhage (0 vs. 1.3%). Also, the cessation of anticoagulant/antiplatelet medication two days before the procedure can contribute to the latter finding. Linden et al. reported no immediate complications, including urinary retention or gross hematuria in 98 patients [12]. Linden’s and ours approach were in common in terms of the applied needle size (18-gauge). Therefore, using 18-gauge needle can help to reduce the immediate complications. Linden employed a triangular arrangement of markers ( at right base, left mid-gland or base and right apex) similar to our approach [12]. Shinohara and Roach also highlighted the importance of avoiding of the urethra to ensure markers are not subsequently lost to voiding [13].

Literature review reflects the controversy in the post-procedural infection rate. Several studies have reported low infection rates (around 2%) [16, 26]; while another study reported higher rates (7.7%) [15]. In the current study, the infection rate was 1%. Compared with the other studies, lower symptomatic infections may root in the applied broad-spectrum antibiotics and the addition of povidone-iodine to the rectal enema just before the procedure. Prophylactic antibiotic is essential in the transrectal approach. However, the optimal antibiotic regimen is not determined. We utilized a combination of ciprofloxacin, an available broad-spectrum bactericide, and metronidazole, which has good coverage on gram-negative bacteria. Most of our patients tolerated the antibiotic regimen well, but three cases ceased metronidazole because of subtle gastrointestinal discomforts. Povidone-iodine seems to be an important factor in diminishing the sepsis rate by reducing rectal bacterial flora.

The optimal anesthesia for FM placement is a matter of debate [16]. This study demonstrated the tolerability of the procedure with sedation using 1–2 mg midazolam. Replacing local anesthetics with general anesthesia can contribute to the reduction in infection rates. The slow injection of IV midazolam, under cardiac monitoring, effectively reduces procedural anxiety and increases patient satisfaction.

Numerous studies have been carried out to identify the factors that predict complications in prostatic FM placement. Kably et al. found that advanced T-stage and metastatic status were the predictive factors, while patients’ age and PSA levels did not play a significant role [16]. However, Igdem et al. discovered that T-stage did not lead to an increase in bleeding complications [11]. This disagreement may be due to small sample sizes and diverse patient populations.

Reports on FM numbers and sites are diverse. Many authors have reported studies using three or four implanted gold markers [6, 27‐30]; on the other hand, there are reports using two elongated markers placed at either side of the prostate to localize the prostate for IGRT [31]. Using three markers seems an acceptable approach to monitor prostate position and volume changes that can occur over time owing to hormone or radiation therapy [32]. Previous studies showed that FM migration within the prostate during radiotherapy is negligible [33, 34]. We employed three FMs placed in a 3D triangular arrangement to facilitate assessment in the three cardinal directions. In this cohort, FM migration was rare and occurred in 2 out of 795 patients (0.2%). It is worth noting that both cases of marker migration occurred in the prostatectomy group shortly after insertion. In both cases, the migrated marker was one of the vesicourethral markers. Therefore, this migration did not clinically influence treatment planning, as the remaining marker adjacent to the vesicourethral junction was deemed sufficient for planning purposes. The higher likelihood of marker migration in this group of patients may be attributed to removing the prostate capsule during prostatectomy surgery. Nevertheless, the ultimate impact on treatment planning decisions was negligible.

In these cases, the IGRT planning was performed based on the other two markers without disruption. The significant advantage of this study is the inclusion of patients after radical prostatectomy. This study demonstrated that inserting a transrectal FM in patients with a history of radical prostatectomy is safe and successful when using anatomical markers like the vesicourethral anastomosis site. Although the risk of complications like sepsis is slightly higher than in non-surgical patients, it remains relatively low. Additionally, the risk of marker migration is also negligible.

This study, in concert with the literature, demonstrated the feasibility, safety, and reliability of FM insertion for prostate IGRT. This study reported a unicentric experience on FM implantation for prostate IGRT. Given lower complications (compared with previous series), our approach can serve as a basis for clinical practice and future studies. The study findings demonstrated that using narrow needles (18-gauge) can reduce the immediate complications, such as urinary retention and pelvic hematoma. Besides, appropriate bowel preparation and irrigation with povidone-iodine in accordance with broad-spectrum antibiotics can significantly reduce the sepsis rates. Generally, TRUS-guided implantation of FMs is safe and well tolerated in the majority of patients. Migration of FMs is very rare and when it does occur, the effect is negligible. The use of three markers provides a tool to monitor prostate position and volume changes and there is convincing evidence that this procedure is safe for image guided radiotherapy and it is highly recommended.