Physics Contribution
Effects of Prostate-Rectum Separation on Rectal Dose From External Beam Radiotherapy

https://doi.org/10.1016/j.ijrobp.2009.07.1679Get rights and content

Purpose

In radiotherapy for prostate cancer, the rectum is the major dose-limiting structure. Physically separating the rectum from the prostate (e.g., by injecting a spacer) can reduce the rectal radiation dose. Despite pilot clinical studies, no careful analysis has been done of the risks, benefits, and dosimetric effects of this practice.

Methods and Materials

Using cadaveric specimens, 20 mL of a hydrogel was injected between the prostate and rectum using a transperineal approach. Imaging was performed before and after spacer placement, and the cadavers were subsequently dissected. Ten intensity-modulated radiotherapy plans were generated (five before and five after separation), allowing for characterization of the rectal dose reduction. To quantify the amount of prostate-rectum separation needed for effective rectal dose reduction, simulations were performed using nine clinically generated intensity-modulated radiotherapy plans.

Results

In the cadaveric studies, an average of 12.5 mm of prostate-rectum separation was generated with the 20-mL hydrogel injections (the seminal vesicles were also separated from the rectum). The average rectal volume receiving 70 Gy decreased from 19.9% to 4.5% (p < .05). In the simulation studies, a prostate-rectum separation of 10 mm was sufficient to reduce the mean rectal volume receiving 70 Gy by 83.1% (p <.05). No additional reduction in the average rectal volume receiving 70 Gy was noted after 15 mm of separation. In addition, spacer placement allowed for increased planning target volume margins without exceeding the rectal dose tolerance.

Conclusion

Prostate-rectum spacers can allow for reduced rectal toxicity rates, treatment intensification, and/or reduced dependence on complex planning and treatment delivery techniques.

Introduction

Definitive external beam radiotherapy (RT) is a prevalent and effective therapy for men with low-, intermediate-, and high-risk localized prostate cancer. Acute and chronic side effects of treatment are generally well tolerated; however, the anterior rectal wall is the major dose-limiting structure. Although the use of intensity-modulated RT (IMRT) has reduced the frequency of acute and chronic rectal toxicity, side effects are still common. With dose-escalated (e.g.,≥78 Gy) IMRT, the rates of acute and chronic Grade 2 or greater rectal toxicity have ranged from 3% to 20% and 5% to 21%, respectively 1, 2. The risk of rectal toxicity depends on the volume of the rectum that receives a high radiation dose. In a large prospective series, the percentage of rectum receiving >70 Gy (V70) correlated with the occurrence of chronic rectal toxicity. For patients in whom the V70 was >26.2% vs. ≤26.2%, Grade 2 or greater chronic rectal toxicity occurred in 54% and 13%, respectively (3).

However, the region of the prostate most at risk of developing adenocarcinoma, the peripheral zone, is located immediately anterior to the rectum. Because of its location, this region typically has the smallest planning target volume (PTV) expansion. Commonly, a 10-mm expansion is applied in all directions, except posteriorly, where expansions of 5–7 mm (or less) are used (4). This relatively small expansion of a mobile pelvic organ necessitates daily image guidance and has led to some concerns about potential underdosing.

From basic radiation protection principles, it is well known that increasing the distance is a simple and effective way to reduce radiation exposure. The interest in recent years to physically separate the rectum from the prostate and thereby reduce the rectal radiation dose has been significant. The prostate-rectum anatomy is accommodating to this concept. Immediately posterior to the prostate is Denonvilliers fascia, a single, fused fascial layer composed of dense collagen, smooth muscle, and coarse elastic fibers (5). This layer is closely adherent to, and fused with, the prostatic capsule and seminal vesicles (6). In a series of 243 radical prostatectomy specimens, tumor progression was seen within Denonvilliers fascia in 19% of cases (6). Importantly, tumor invasion beyond Denonvilliers fascia was never seen. Therefore, during radical prostatectomy, dissection should be performed posterior to Denonvilliers fascia (6). The loose, areolar, adipose tissue of the mesorectum lies just behind Denonvilliers fascia, followed by the muscular layers of the rectal wall, and then the rectal mucosa. This loose, areolar tissue that separates the prostate and rectum is fairly easy to develop and separate. Injection of saline in this space before prostate cryotherapy is a recommended practice 7, 8. After the cryotherapy procedure, the saline is reabsorbed.

Just as the plane posterior to Denonvilliers fascia is developed during radical prostatectomy and cryotherapy, it is an ideal plane to expand before RT. To date, at least three approaches to expand this space have been applied in pilot clinical work. First, Noyes and Noyes (9) injected collagen between the prostate and rectum in 10 men before prostate IMRT. Prada et al.10, 11 injected hyaluronic acid between the prostate and rectum in 27 patients before high-dose-rate brachytherapy and in 32 patients after low-dose-rate brachytherapy. A Phase I clinical trial is investigating a biodegradable balloon implanted between the prostate and rectum before RT (12).

Synthetic polyethylene-glycol (PEG)-based hydrogels might also be useful as prostate-rectum spacers. These hydrogels (which are >90% water by weight) are thin liquids when injected, but then polymerize in situ to form a soft hydrogel after the two precursor solutions mix. Although a variety of PEG hydrogels with various properties exist, we used one PEG hydrogel (DuraSeal, Confluent Surgical, Waltham, MA) as an example of this class of compounds (13). DuraSeal is Food and Drug Administration approved as an adjunct to surgical closure of the dura (to reduce the incidence of cerebrospinal fluid leakage). DuraSeal remains intact for 4–8 weeks after application, is degraded by hydrolysis of ester bonds, and is then excreted renally.

Despite significant interest from both academia and industry, no careful analysis of the dosimetric effects of prostate-rectum spacers has been done. It is unclear how much prostate-rectum separation is needed, what rectal dose reduction can realistically be achieved, and whether this benefit is applicable to all patients (i.e., those receiving prostate-only treatment vs. those receiving treatment to the prostate, seminal vesicles, and pelvic nodes). Also, the potential for harm from this practice should be considered. In the present study, using cadaveric specimens and RT plans from clinically treated patients, we have described and characterized the dosimetric effects of creating prostate-rectum separation. Although we believe that PEG hydrogel compounds have advantages for this application, our primary goal was to characterize the effects of prostate-rectum separation, independent of the particular substance or technique used.

Section snippets

Preparation and imaging of cadaveric specimens

Using an approved protocol, two refrigerated, unfixed, unfrozen, cadaveric specimens were obtained within the first 3 postmortem days. Before intervention, the specimens underwent computed tomography (CT) simulation (Philips Brilliance Big Bore CT, 3-mm slices, 120 kVp, 300 mA, 60 cm field of view). Under endorectal ultrasound guidance (7.1 MHz, B-K Medical 2101 Falcon, 8658, 4–9-MHz endorectal probe), an 18-guage, 3.5-in. needle was advanced through the perineum and into the tissue plane

Implants well visualized on CT, ultrasonography, and MRI

On axial, T2-weighted MRI, the PEG hydrogel was clearly visible as a hyperintense region between the prostate and rectum (Fig. 1a). The mean separation was 12.5 mm. The sagittal MRI (Fig. 1d) showed that the separation was consistent along the length of the prostate and that separation also developed between the seminal vesicles and the rectum. On the axial CT slices (Fig. 1b), the hydrogel was seen as a water-density region between the prostate and rectum. On ultrasound imaging (Fig. 1c), the

Discussion

Separating the rectum from the prostate significantly reduces the link between the rectal and prostate radiation dose. Clinically, we can consider the potential utility of this from several perspectives. First, and most obviously, one could simply integrate this technique with the current paradigm of daily, image-guided, highly conformal, dose-escalated RT. As shown in the present study, extremely low rectal doses can be achieved and, therefore, a very low risk of rectal toxicity would be

Acknowledgments

We acknowledge Cory Brayton, D.V.M., for reviewing and scoring the mouse histology sections; Ming Zhao, Ph.D., Michelle A. Rudek, Pharm.D., Ph.D., Sarah Reinhardt, B.S., and Aleksandr Mnatsakanyan, M.D, for performing the chromatography analysis.

References (23)

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In vitro work was supported in part by National Institutes of Health Grants P30CA006973 and UL1RR025005.

Conflict of interest: Johns Hopkins University, Department of Radiation Oncology and Molecular Radiation Sciences received an unrestricted gift from Augmenix. These funds were used, in part, to support this work. None of the authors have a financial interest in Augmenix or any other conflicts of interest.

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