Transperineal versus transrectal prostate fiducial insertion in radiation treatment of prostate cancer: a systematic review and meta-analysis
Article information
Abstract
Purpose
To provide more accurate and definitive conclusions regarding the clinical and technical complications associated with the transperineal (TP) and transrectal (TR) approaches, a comprehensive review of observational studies and randomized controlled trials was conducted. This systematic review covered all eligible studies to facilitate a thorough comparison of complications linked to the two fiducial marker insertion methods, TP and TR.
Methods
A comprehensive search of the literature was conducted, encompassing databases such as PubMed, Embase, and the Cochrane Library, up to July 7, 2023. The relative risk and 95% confidence interval were utilized to evaluate the diagnosis and complication rates.
Results
The final selection for the methodological quality analysis included 13 observational studies that utilized TP and TR gold fiducial insertion approaches. The meta-analysis revealed significantly lower risks of urinary tract infections (UTI) and rectal bleeding with the TP approach.
Conclusion
The use of both TP and TR techniques for placing gold seed fiducial markers has proven to be an effective, safe, and well-tolerated method for image-guided radiation therapy in prostate cancer patients. A significant benefit of the TP technique is its ability to avoid rectal puncture, thereby reducing the risk of UTIs. Although the incidence of UTIs and rectal bleeding associated with the TR method is relatively low, these complications can disrupt patient wellbeing and potentially cause delays in treatment.
Introduction
Image-guided radiotherapy (IGRT) reduces the risk of geographical misses in target irradiation. Therefore, IGRT enables the administration of higher radiation doses without increasing rectal toxicity. Fiducial markers are commonly used in IGRT for treating prostate cancer to improve accuracy. Gold fiducial markers have been shown to be effective not only in image-guided high-dose radiation therapy but also in postprostatectomy IGRT. These markers are essential for monitoring both inter- and intra-fractional movements of the prostate [1,2].
In IGRT for prostate cancer, gold fiducial markers can be implanted using two primary approaches: the transperineal (TP) approach and the transrectal (TR) approach. The TR approach is more commonly used for placing fiducial markers, largely because it is considered more comfortable for patients. Typically, patients prefer the supine position with a left lateral decubitus orientation over the lithotomy position. Additionally, operators favor the TR approach for inserting fiducial markers because it employs the same equipment and procedural setup as TR biopsies [1].
While numerous studies have utilized the TR approach for gold marker insertion, noting its low risk of major complications and minimal risk of septic toxicity, concerns remain about the potential for urinary tract infections (UTIs) and urosepsis. These concerns are primarily due to the significant risk of post-implantation infection, which is often linked to the presence of pathogens in the fecal reservoir. Although the TR approach is generally patient- and operator-friendly, it has faced criticism due to infrequent but notable complications, such as occasional UTIs and rectal bleeding [3,4].
Some recent studies have attempted to reduce the incidence of urosepsis by utilizing the TP approach. However, the number of reported studies on the TP approach remains limited. The TP approach was originally introduced for prostate biopsy with the dual purpose of improving detection rates and safety. Although several studies have aimed to compare complication rates associated with TP and TR prostate biopsy approaches, the findings have been inconsistent regarding the complication rates of these two approaches [5].
To the best of the authors’ knowledge, no meta-analysis has specifically assessed the safety of the TP and TR fiducial marker insertion methods. The majority of available studies are observational and primarily focus on clinical and technical complications. To draw more accurate and definitive conclusions about the rates of clinical and technical complications associated with the TP and TR approaches, a comprehensive review was conducted of both observational studies and randomized controlled trials (RCTs). This systematic review incorporated all eligible studies to enable a thorough comparison of complications linked to the two fiducial marker insertion methods, TP and TR.
Materials and Methods
Search Strategy
This review adhered to the guidelines in the PRISMA 2020 statement for reporting systematic reviews [6]. A comprehensive search of the literature was conducted across databases including PubMed, Embase, and the Cochrane Library, up to July 7, 2023. The search criteria incorporated the terms "prostate cancer" and "fiducial marker," in conjunction with "perineum." "transperineal," "rectum," or "transrectal." These searches were restricted to articles available in English, studies involving human subjects, and those focused on male populations.
Two authors, SS Hong and SH Bae, independently reviewed the titles and abstracts of the identified articles, adhering to predefined inclusion and exclusion criteria. When discrepancies occurred between the assessments of the two authors, they achieved consensus through discussion.
Inclusion Criteria
The studies included in the review were required to meet all the following criteria: (1) they were designed as an RCT, cohort, or case-control study, (2) they involved patients who underwent prostate fiducial insertions, (3) they examined both the TP and TR intervention methods, (4) they assessed the clinical and technical complications associated with these two approaches, and (5) they reported incidence rates along with their 95% confidence intervals.
Data Extraction
In cases where studies involved overlapping data sets, the most recent and relevant results were chosen after detailed discussions between the two authors. They independently reviewed the titles and abstracts of all articles according to predefined inclusion criteria. The full-text articles were then independently assessed by the two authors to ascertain their compliance with the inclusion criteria. Data extraction was performed independently by the two authors using a standardized form. The decision to include studies in the final analysis was made after a thorough evaluation and discussion among all authors. To ensure the integrity of the meta-analysis and prevent the inclusion of duplicate data, references and data from each study were meticulously cross-checked.
The essential elements gathered from the included studies comprised the following: the last name and country of the first author, the publication year, the patient's age, study design, study population, the number of patients in each or both groups, prostate-specific antigen level, prostate volume, number of fiducials, and the covariates included in the analyses. For observational studies, either the relative risk (RR) or odds ratio (OR) that was adjusted for the greatest number of confounders was extracted. If neither the RR nor OR was available, the authors obtained the raw data and calculated these measures themselves to estimate the diagnostic accuracy of the TP and TR approaches.
Assessment of Methodological Quality
In the meta-analysis, the evidence provided by observational studies and RCTs was merged. This meta-analysis incorporated data from recent studies, and the methodological quality was assessed using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool. Additionally, risk of bias figures were generated using the robvis R package [7].
Assessment of Heterogeneity
All included studies were either cohort or observational studies; therefore, the incidence rate was utilized to estimate the safety of TP and TR approaches. Statistical heterogeneity was assessed using Cochran’s Q test and the I2 statistic. Significant heterogeneity between studies was indicated by a Cochran’s Q statistic P<0.1 or an I2 statistic >50%. Conversely, a non-significant chi-square test result (P≥0.1) or an I2 statistic ≤50% suggested a lack of evidence for heterogeneity. It is important to recognize that this does not necessarily imply homogeneity but rather indicates insufficient statistical power to detect heterogeneity. Thus, a random-effects model was employed for the analysis.
Assessment of Potential Publication Bias
The funnel plot, which utilizes standard error as the measure of study size, was employed to assess publication bias. In the absence of publication bias, the combined effect size from the studies exhibited a symmetrical distribution.
Results
Study Selection
The initial search yielded a total of 836 articles retrieved from various electronic databases, including 253 from PubMed, 15 from Cochrane, and 568 from Embase. Next, 192 studies that contained duplicate data or were found in multiple databases were eliminated. The titles and abstracts of the remaining 644 studies were screened, resulting in the exclusion of those that were not relevant to the topic under investigation. Subsequently, a more detailed review led to the exclusion of abstracts from five additional studies.
Of the remaining articles, 30 were excluded because they did not align with the primary focus of the investigation. Additionally, five studies were eliminated due to duplication from the same institutions, and two studies were excluded because they primarily consisted of technical reviews. An additional case report was excluded because it pertained to toxicity following fiducial marker insertion. Therefore, the final selection for methodological quality analysis included 13 studies. Fig. 1 presents the study selection process).
Flowchart of study assessment and selection.
The key attributes of the 13 observational studies are presented in Table 1. It is important to note that none of the studies included in this analysis were RCTs. The studies covered a period from 2009 to 2023. The sample sizes varied significantly, ranging from 51 to 795 patients. The cumulative population included in this meta-analysis totaled 4,169 individuals, with 2,624 patients in the TP group and 1,545 in the TR group.
Characteristics of observational studies of TP and TR fiducial insertions
Outcomes
Information regarding the 13 observational studies is presented in Fig. 2, and the analytical outcomes are shown in Table 2 and Fig. 3.
Comparison of the incidence of complications after TP and TR fiducial insertion in patients with prostate cancer
Forest plot and meta-analysis for clinical complications and technical aspect between transperineal (TP) and transrectal (TR) fiducial insertion methods [8-15,17-21].
A. Urinary symptoms: Comparison of the incidence of urinary symptoms between TP and TR methods is shown. B. Urinary tract infections (UTI): Analysis shows the relative risk of UTIs associated with each insertion technique. C. Rectal bleeding: Evaluation of the occurrence of rectal bleeding in patients undergoing TP versus TR fiducial marker insertion is shown. D. Technical aspects: Assessment of technical complications, including fiducial migration and placement accuracy, between the two approaches is shown.
Concerning urinary symptoms, a comparison between the TP and TR approaches involved 46 (1.8%) and 158 (10.2%) patients, respectively. Hematuria emerged as the most common symptom, often accompanied by voiding difficulties. Hematospermia was reported in 12 patients (0.5%) in the TP group and 35 patients (2.3%) in the TR group. UTIs occurred in two patients in the TP group and 35 patients (2.3%) in the TR group, with additional complications including sepsis, fever, bacteriuria, and epididymitis, each recorded at a frequency of 1. Rectal bleeding was not observed in the TP group, but was present in 53 patients (3.4%) in the TR group. The statistical analysis indicated no significant difference in the incidence of urinary symptoms such as dysuria, urinary hesitation, or urinary frequency between the TR and TP groups (P=0.790). However, significant differences were noted in the rates of UTIs and rectal bleeding between the TR and TP groups (P=0.006 and P=0.019, respectively).
There were 18 technical failures, which included six cases of migration and seven cases of missing fiducials, with 10 occurrences in the TR group and eight in the TP group. Similarly, there was no statistically significant difference in the incidence of technical complications, such as migration, discrimination failure, or missing fiducials, between the TR and TP groups (P=0.065).
Discussion
The incidence of multidrug-resistant infections in TR prostate fiducial implantation procedures has been increasing, mirroring the trends seen in TR biopsy procedures. Despite the use of prophylactic antibiotics, febrile infection rates typically range from 1% to 4% [8]. Bacterial sepsis is notably the most severe complication associated with gold marker implantation. The practice of administering antibiotics before implantation is widely recognized as a strategy to reduce the risk of UTIs. However, it is crucial to recognize the similarities between prostate biopsy and TR fiducial implantation. The most significant risk factor for urosepsis following a prostate biopsy is the presence of fluoroquinolone-resistant organisms in the fecal reservoir. Typically, these resistant bacteria are responsible for 50%-90% of infection cases following prostate biopsies [8].
Recently, the implantation of TP fiducials has been recommended to reduce the incidence of urosepsis. Most studies evaluating the toxicities and complications associated with this procedure have been retrospective, often involving a significant recall period, which could lead to the over- or underestimation of symptoms.
The incidence of urosepsis appears to be higher following TR procedures (1%-7%) than after TP procedures. In a study conducted by Loh et al. [9], 11.6% of patients reported experiencing chills and fevers following the TR procedure, with 7.7% requiring antibiotics for urinary infections and 2.8% being admitted to the hospital due to urosepsis associated with the TR approach.
Mahdavi et al. [10] reported that eight patients (1% of the overall cohort) developed sepsis following the TR procedure. These cases of sepsis were marked by symptoms including a fever exceeding 38.5°C, severe chills, and myalgia unresponsive to over-the-counter medications, necessitating the use of oral antibiotics. The incidence of sepsis was not significantly higher among patients with a history of radical prostatectomy. Of these patients, seven were treated with intravenous antibiotics in the emergency department and discharged within 12 hours. One patient required a longer course of antibiotic therapy and was discharged within 2 days [10].
One research team reported that two patients (1.18%) developed UTIs following the TR procedure [11]. In another study that utilized a TR technique, 3% of patients experienced symptoms such as fever, shivering, or urogenital infections, including severe grade 4 septicemia [12]. Lastly, a retrospective study evaluating complications after TR fiducial marker implantation in 209 patients found that 1.9% of the patients experienced fever [13].
A large-scale study involving 579 patients conducted by Saad et al. [14] reported that only two patients experienced UTI complications, indicating a very low incidence rate of less than 0.5%. Furthermore, Moman et al. [8] found that among 402 patients who underwent TR fiducial marker implantation, two developed urosepsis, which is considered a grade 3 toxicity in the context of image-guided radiation therapy.
A retrospective study conducted by Igdem et al. [15] reported the side effects experienced by 135 patients who underwent TR gold marker implantation, utilizing questionnaires to collect data. Three patients in this cohort experienced symptomatic urosepsis, confirmed by urinary culture, which constituted 2.2% of the total patients. These patients were administered additional antibiotics, which normalized their body temperatures within a few days. Importantly, none of these cases necessitated hospital admission. One of these patients developed asymptomatic bacteriuria during the follow-up period but spontaneously recovered after 6 months [15].
It is noteworthy that rectal bleeding does not appear to be a significant concern with the TP approach. However, in the TR approach, a study by Gill et al. [12] reported that rectal bleeding occurred in 26 patients, which constitutes 11% of the cases. Among these, one patient required a blood transfusion, and five experienced bleeding that persisted for more than 2 weeks [12]. A retrospective study by Langenhuijsen et al. [13] on complications following TR fiducial marker implantation in 209 patients found that 9.1% of the cases reported rectal bleeding.
Furthermore, Igdem et al. [15] reported that five patients, representing 4% of their study population, experienced rectal bleeding. The duration of the bleeding was limited to 1 day, and the condition resolved without any medical intervention. Additionally, Sen [16] observed rectal bleeding in two patients, which also accounted for 4% of their study cohort. Notably, none of the patients in this group developed fever or hematospermia.
In this meta-analysis, which included 13 observational studies, there were no significant differences in urinary symptoms such as hematuria, urinary obstruction, or urinary hesitation between the TR and TP groups. Hematuria, a frequently observed urinary symptom, had occurrence rates that aligned with those reported in the literature, ranging from 10% to 18.5% and 3.8% to 15% respectively [13,17-20]. Notably, most cases of bleeding-related symptoms resolved spontaneously without the need for specific treatment or hospital admission.
A study by Gill et al. [12] documented that hematospermia occurred in 10% of 234 patients who underwent the TR approach, and hematuria was observed in 13% of the same cohort. This study reported findings from a questionnaire distributed to 234 patients after completing their treatment, revealing that 32% of the patients developed at least one new symptom following the procedure. These symptoms included increased frequency in 16% of the cases, and hematuria, rectal bleeding, dysuria, and hematospermia in 9% to 13% of cases. Additionally, pain, obstruction, and shivering were reported in 3% to 4% of cases, and 9% of patients experienced symptoms lasting more than two weeks. In contrast, studies assessing patients before starting radiation therapy reported fewer complications.
Igdem et al. [15] reported that hematuria was observed in 20 patients, with 14 experiencing episodes that lasted no more than 1 day. Four patients reported hematuria lasting more than 3 days. Notably, none of the patients required additional medical interventions. Furthermore, no patients exhibited vegetative symptoms such as sweating or hypotonia, and there were no reports of urinary retention.
There were no statistically significant differences in technical complications between the two groups, despite the notably low incidence rate. In a study by Moman et al. [8], marker migration resulted in the discontinuation of treatment for five patients. Ohta et al. [21] reported that fiducial marker migration occurred in 0.6% of 524 markers in the TR group and in 1.1% of 182 markers in the TP group, with no significant difference between the groups (P>0.05). Another study documented a seed migration rate of 0.32%, with two markers migrating out of 626 implanted [11]. Saad et al. [14] reported that in a large series of TP fiducial implantations, seeds were missed in 24 out of 579 patients (4.1%). Kably et al. [20] noted that two markers were placed just outside the prostate capsule, and one marker was subsequently lost. In a study conducted by Mahdavi et al. [10] involving 795 patients, only two experienced marker migration shortly after insertion; no fiducial migration was reported during the course of radiotherapy. For these two patients, other major complications were recorded, but there was no impact on treatment planning, delivery, or side effects.
In the study by Ohta et al. [21], both technical success and pain scores were evaluated. The TR group reported lower pain scores compared to the TP group. The technical success rates were 100% (262/262) for the TR group and 99% (90/91) for the TP group. Saad et al. [14] noted that the fiducial insertion procedure was discontinued for two patients due to pain, while two others required additional sedation. Furthermore, an extra seed was placed in two patients because of difficulties encountered with ultrasonographic placement during the procedure. These findings suggest that the TP approach may be linked to higher pain levels and a reduced success rate of the procedure. Igdem et al. [15] conducted a retrospective questionnaire-based study, revealing that 68% of patients found the fiducial marker insertion procedure less painful than a prostatic biopsy. In contrast, 19% reported pain levels similar to those of a biopsy, and 13% experienced more pain.
In the context of medical procedures, the incidence of infection and rectal bleeding associated with the TP approach is relatively low. However, these complications can be bothersome to patients and may potentially lead to treatment delays. Additionally, there is growing concern about the emergence of antibiotic-resistant infections, a trend increasingly observed in patients undergoing TP fiducial insertion [14].
This review has several limitations. First, it relies exclusively on observational studies. Igdem et al. [15] and Loh et al. [9] reported instances where subjects were missing due to unanswered questionnaires sent by mail for symptom assessment several weeks after the procedure. This could have led to memory errors, as the surveys were conducted a year after the procedure. Additionally, the analysis focused on evaluations from subjective patient questionnaires rather than on complications assessed by medical professionals. Furthermore, Moman et al. [8] and Ohta et al. [21] indicated that the TR approach was used in the initial years, followed by the TP approach in subsequent years. This sequence may introduce bias due to technical improvements over time by the practitioners.
In conclusion, the placement of gold seed fiducial markers using both TP and TR techniques is an effective, safe, and well-tolerated method for IGRT in patients with prostate cancer. One notable advantage of the TP technique is its ability to circumvent rectal puncture, thus reducing the risk of infections. While the rates of UTIs and rectal bleeding linked to the TR approach are relatively low, these complications can disrupt patients’ well-being and potentially lead to treatment delays.
Notes
Author Contributions
Conceptualization: Hong SS, Bae SH. Data acquisition: Hong SS, Bae SH, Hwang J. Data analysis or interpretation: Hong SS, Lee EJ. Drafting of the manuscript: Hong SS, Bae SH. Critical revision of the manuscript: Hong SS, Bae SH, Hwang J, Lee EJ. Approval of the final version of the manuscript: all authors.
No potential conflict of interest relevant to this article was reported.
Acknowledgements
This work was supported by the Soonchunhyang University Research Fund.
References
Article information Continued
Notes
Key point
This systematic review compared the clinical and technical complications of transperineal (TP) and transrectal (TR) fiducial marker insertion methods for prostate cancer treatment. A meta-analysis of 13 observational studies found that the TP approach had significantly lower risks of urinary tract infections and rectal bleeding compared to the TR approach. Both techniques were effective and well-tolerated, but the TP method's advantage in avoiding rectal puncture made it safer, despite the TR approach being more commonly used due to patient comfort and procedural familiarity.