Original paper
Permanent prostate brachytherapy extracapsular radiation dose distributions: analysis of a multi-institutional database

Purpose

Permanent prostate brachytherapy represents a highly efficacious treatment for clinically localized prostate cancer with a defined relationship between dosimetric quality, biochemical outcome and complications [1,2]. Previous studies have demonstrated that long-term cancer control is related to intra-prostatic radiation dose and periprostatic treatment margins [3-6]. However, treatment margins can vary markedly between patients with comparable intra-prostatic dose distributions [5]. Because brachytherapy dose decreases by as much as 20 Gy per millimeter at the periphery of the target volume, as many as 50% of patients with a pre-treatment prostate specific antigen (PSA) < 10 ng/mL manifest extracapsular extension (EPE), and the radial extent of EPE is usually in the range of 2-5 mm [7-9], periprostatic treatment margins accomplished by either monotherapeutic brachytherapy and/or the addition of supplemental external beam radiation therapy (XRT) are necessary to ensure geographic coverage of potential sites of EPE.

Currently, there is interest in minimizing and/or eliminating supplemental XRT in patients with higher risk disease [10]. A reduction/elimination of supplemental XRT will mandate adequate brachytherapy periprostatic treatment margins to address possible EPE and to maximize long term cancer control. At the present time, there is no consensus regarding the extent of periprostatic margins or the dose necessary to sterilize EPE, even among brachytherapy experts [11]. Previously in the Pro-Qura database (Pro-Qura, Seattle, WA, USA), we have documented substantial differences in overall intraprostatic sector dosimetric quality [12]. In the current Pro-Qura evaluation, we evaluate extracapsular dose distributions in patients implanted with permanent prostate brachytherapy. Hopefully, analysis of the Pro-Qura database and other multi-institutional studies will illustrate potential population-based inadequacies and help establish national standards of care.

Material and methods

From August 1999 to December 2008, 4547 post-implant computed tomography (CT) scans in the Pro-Qura database were available for analysis. The CT scans originated from 129 Pro-Qura participating brachytherapists. Patients implanted at the authors institutions are not part of the Pro-Qura database. The original post-implant prostate dosimetry was reported in terms of a V₁₀₀ (the percentage of the prostate volume covered by the prescription dose) and D₉₀ (the maximum dose covering 90% of the prostate volume). All implants were pre-planned. Post implant CT was performed at a median of 30 days following brachytherapy.

The Pro-Qura technique for post-implant dosimetric analysis has been described in detail [13]. In this study, using the Pro-Qura defined post-implant prostate volume, a 5 mm, 3-dimensional periprostatic annulus was constructed around the prostate gland (except posteriorly where a 2 mm margin was used), and evaluated in its entirety and in separate sectors to include the anterior, posterior, inferior and right/left apical aspects. Dose to the periprostatic annulus was defined in terms of an annular V₁₀₀. Figure 1 is an illustration of the periprostatic annulus and the individual segments.

Of the 4547 patients, 3094 (68.0%) were implanted with ¹²⁵I, 1437 (31.6%) with ¹⁰³Pd and 16 (0.4%) with ¹³¹Cs. For ¹²⁵I, 84.3% of patients underwent monotherapy (144-145 Gy) and 15.7% a boost (110 Gy) for ¹⁰³Pd, 67.4% of patients underwent monotherapy (125 Gy) and 32.6% a boost (90-100 Gy). For ¹³¹Cs, 62.5% of patients underwent monotherapy (115 Gy) and 37.5% a boost (84 Gy). Because of small patient numbers, ¹³¹Cs patients were not included in the analysis of periprostatic treatment margins, but were included in Table 1 for completeness.

Statistical analysis was performed using Predictive Analytics Software (PASW), Statistics Version 17.0 (SPSS Inc., Chicago, IL, USA). The means for continuous variables were compared using independent-samples t-tests, and one-way analysis of variance and chi-square tests were used to compare distributions within categorical variables. Probabilities of deviation from the null hypothesis of no significant differences were marked if statistically significant, p < 5%.

Results

Treatment and summary dosimetric data for the 4547 patients in the study population are summarized in Table 1. There was no statistically significant difference in prostate V₁₀₀ or D₉₀ when stratified by isotope or monotherapy vs. boost. In addition, there was no difference in prostate size or number of implanted seeds when stratified by isotope. However, for both ¹²⁵I and ¹⁰³Pd, prostate glands were statistically larger and more seeds were implanted in the monotherapy vs. the boost cohorts.

Table 2 summarizes the mean margin sector analysis for V₁₀₀ for the 4547 evaluated patients. For all sectors, the mean V₁₀₀ was 62.8%. The V₁₀₀ at the base (51.6%) was less than the apex (73.5%) and the midgland (65.9%). In addition, for the group as a whole, the anterior V₁₀₀ (45.7%) was less than the lateral (68.8%) and the posterior (75.0%) V₁₀₀. Tables 3 and 4 describe the mean margin sector volumes, and V₁₀₀ for ¹²⁵I and ¹⁰³Pd. The V₁₀₀ for ¹²⁵I was greater than the V₁₀₀ for ¹⁰³Pd both overall, and when evaluated by apex/ midgland/base and anterior/lateral/posterior sectors.

Discussion

Despite favorable long term biochemical control rates in patients treated with permanent prostate brachytherapy, the definition of a technically adequate implant including periprostatic dose distributions remains somewhat unclear [14,15]. However, data suggests that permanent cancer control is related to intraprostatic radiation dose and periprostatic treatment margins [3-6].

Since extracapsular treatment margins can vary substantially in patients with high quality intraprostatic brachytherapy [5], analysis of annular brachytherapy doses will become mandatory as supplemental XRT is phased out of higher risk brachytherapy protocols. Periprostatic doses are attainable via either a brachytherapy approach that includes generous periprostatic treatment margins and/or the addition of XRT [3,4,11].

Data suggests that periprostatic dose impacts the likelihood of treatment success [5,6,9,16]. Choi et al. demonstrated that the anterior treatment margin in low risk prostate cancer patients was statistically significant in predicting biochemical outcome [5]. In a more sophisticated study, Crook et al. using magnetic resonance imaging (MRI) defined prostate contours reported dosimetric coverage of the prostate gland with 2-, 3-, and 5-mm margins in patients biochemically controlled and in those with biopsy proven recurrence [16]. The mean D₉₀ and V₁₀₀ were statistically lower in the 2-, 3-, and 5-mm expansions in patients with biopsy proven local failure. Among patients without and with local recurrence, the mean V₁₀₀ in the 5 mm-group were 77.4% and 72.4% (p = 0.045). Merrick et al. reported an annular V₁₀₀ of 95.1% in a series of ¹²⁵I and ¹⁰³Pd patients [6]. In that study, margin status did not correlate with biochemical control, probably as a result of robust intraprostatic and annular dosimetry. In the current Pro-Qura study, the overall annular V₁₀₀ was 62.8% for all evaluated patients (65.2% for ¹²⁵I and 57.6% for ¹⁰³Pd), which compared to the above mentioned results from high volume brachytherapy centers are probably inadequate for monotherapeutic approaches, especially those with higher risk disease. Previously, it has been reported that ¹²⁵I resulted in higher annular doses compared to ¹⁰³Pd [6], but did not result in biochemical control differences.

Although the radiation dose needed to sterilize periprostatic disease is unknown, the dose to control extraprostatic disease is probably significantly less than the threshold intraprostatic doses, because the ratio of extraprostatic to intraprostatic cancer is in the range of 0.4% [17]. Eventually, predictive modeling and improved imaging may enable prostate brachytherapists to tailor treatment margins on a case by case basis [18,19]. Until these technologies become available, a 3-5 mm periprostatic treatment margin appears prudent [6,9,16].

A strength of our analysis is the diverse representation of a large number of community brachytherapy practices with post-implant dosimetry performed with a consistent and highly reproducible technique. However, a limitation of the study is that once stored in the Pro-Qura database, the individual brachytherapist responsible for the CT scan is no longer identifiable and as such a learning curve analysis for margin assessment was not possible. Most importantly, there are limitations to the Pro-Qura post-implant dosimetric technique. Because the Pro-Qura technique uses the pre-implant TRUS determined prostate volume, it is highly probable that the actual annular doses are less than what is reported in this study. In addition, due to the rapid dose fall off at the periphery of the target volume, annular dose distributions are very sensitive to contouring errors. In the current study, this variable has been minimized [8]. Finally, Pro-Qura was established as a preplanning and dosimetry service, and does not have access to outcomes including biochemical control and/or complications. This eliminates our ability to establish a dose response curve for the annular dose necessary to secure long-term biochemical control.

Conclusions

The optimal extracapsular brachytherapy dose and radial extent remains unknown, but will prove increasingly important with reductions and/or elimination of supplemental external beam radiation therapy. The Pro-Qura database demonstrates periprostatic annular doses that are not as robust as those in selected high volume brachytherapy centers, and may be inadequate for optimal biochemical control following monotherapeutic brachytherapy, especially in higher risk patients.

Conflict of interest

Peter Grimm is an owner of Pro-Qura.

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