The treatment of prostate cancer with external beam radiation can be hindered, or even contra-indicated, based on unfavorable patient anatomy and/or uncorrectable daily variations in organ position.  Since radiation treatment plans are based on fixed internal and external anatomy, changes in anatomy may lead to insufficient doses to the target area and/or increased doses to surrounding critical structures.

In the treatment of prostate cancer, radiation doses delivered of greater than 70 Gy, have demonstrated better local tumor control.  Increasing the dose above 70 Gy, however, is limited by the toxicity and side-effects that could result to surrounding critical structures such as the rectum and bladder.  New radiation treatment methods such as 3D-conformal radiation therapy (CRT), intensity modulated radiation therapy (IMRT), and image guided radiation therapy (IGRT), have allowed higher doses to be delivered to the target volume, while minimizing the dose to nearby healthy tissue.  Accurate target localization and patient set-up reproducibility become even more critical with these advanced treatment methods, which have tightly constructed isodose lines and much smaller treatment margins.

Organ Motion (Intra/Inter-fractional Variation)

External patient positioning systems attempt to minimize anatomical variations by providing a secure and reproducible scaffolding, allowing the patient to comfortably maintain a relatively stable external position.  However, neither CRT/IGRT/IMRT, nor the external positioning systems, can compensate for daily internal anatomy variations and organ movement due to breathing, rectal peristalsis, and rectal gas, which have been shown by Little et al (2003) to be the major component of variation in target localization.  Beard et al (1996) reported the intrinsic motion of the prostate gland can be as much as 5 mm in the anterior to posterior direction due to rectal peristalsis.  This has led to an additional 3 to 5 mm margin being added to the radiation field to account for prostate motion, along with 2 to 5 mm for setup error and dose buildup each, for a total margin of 10 to 15mm to allow for the dose to reach 100% of the prescribed dose.  If internal prostate motion is not addressed, it can lead to under-dosing of the target, and over-dosing of healthy surrounding tissues.  

Variations in rectal volume appear to be the primary contributing factor to inter and intra-fractional prostate motion as well as inter-fractional prostate/SV position due to discrepancies in rectal distention during RT.  Crevoisier et al.  (2005) found that shifts in AP prostate and seminal vesicle position are highly correlated with rectal filling and, to a lesser extent, with bladder filling.  These shifts in internal organ positions are not detected by alignment techniques based on skin marks or portal imaging (bony anatomy alignment).  On the basis of a retrospective analysis of 127 patients, Dr. Crevoisier confirmed the hypothesis that rectal distension as seen on the planning CT scan can increase the risk of local and biochemical failure (when the rectum is shown to be less distended during RT vs. planning CT).  Furthermore, rectal distension appears to have an even greater impact on patient outcomes than disease risk group.  Frank et al. (2008) concluded that prostate AP and SI displacement during treatment correlated with the rectal volume changes in 73% and 27% of daily CT scans taken in his 15 patient analysis.

Cine MRI images and CT on rails technology have been used to evaluate the movement of transient rectal contents (primarily gas) during a specific time period and the effect of these contents on the prostate position has been significant.  

Ogino et al. (2008) reviewed the effects of evacuating rectal gas prior to RT delivery.  Patients were asked to evacuate their rectums by inserting and removing their index finger to evacuate the rectal gas before therapy.  Dr. Ogino concluded that the vector of the prostate and seminal vesicle displacement for the rectal gas removal group was significantly smaller than in all patients.  Prostate movement resulting from extreme distension of unstable rectal gas displaced the prostate up to 1.2cm posteriorly after gas removal.  These findings prove that controlling rectal volume consistently is vital to reproducible RT treatment irrespective of IGRT utilization.

Recently Langen et al. (2008) found that it may not be possible to use X-rays obtained before and after each treatment (traditional IGRT) to estimate the extent and effect of target motion because only two observations are made during intervals that last several minutes.  Dr. Langen utilized Calypso technology to study intra-fractional motion and it’s potential impact on treatment delivery.  Using Calypso GPS transponder beacons to track the prostate motion real time, they found that one-quarter of all observations made 10 min after patient alignment showed displacements > 3mm. Various types of motion, such as drift and transient, were thought to be the result of gradually moving rectal content away from the prostate, as well as general rectal peristaltic motion.

Motion Control and Plan Reproducibility

Internal organ variation (not just motion) and movement can be solved with the use of an endorectal balloon (ERB) for prostate immobilization.  D’Amico et al (2001) and McGary (2001) have demonstrated that the use of an ERB can reduce prostate motion during treatment from 4 mm to less than 1 mm.  D’Amico demonstrated that the prostate moves more than 3 mm within 10 minutes, 25% of the treatment time.  He reported that use of an ERB can reduce the chances of large, random shifts of greater than 10mm.  

D’Amico concluded that the posterior margin necessary on the lateral fields to ensure dosimetric coverage of the entire prostate gland could be safely reduced to 5 mm.  Teh et al have also reported prostate motion to be ~1 mm using an ERB.  Daily treatment plan compensations and the problems associated with these changes are virtually eliminated as a result of the reproducible prostate immobilization achieved with an ERB.  Moreover, it allows the margins of normal tissue around the treatment target, which must be treated in anticipation of daily movement, to be significantly reduced (D’Amico et al, 2001).  

IMRT planning is based on fixed anatomy calculation leaving a large level of uncertainty in the reproducibility of the treatment plan (is your planned dose your delivered dose?).  Watcher et al (2002) reported when using a balloon device, rectum filling variations and maximum anterior-posterior displacements of the prostate were reduced significantly, leading to a reduction in DVH variations during treatment.  Plans were regenerated during therapy for 10 consecutive patients using repeat CT scans.  The balloon led to a significant reduction in partial posterior rectal wall volumes included in the high-dose regions, without significant changes at the anterior rectum wall in cases of irradiation of the prostate only.  

Vapiwala et at (2009 ASTRO Abstract) evaluated the impact of bladder and rectal volume variability on the original planning dose-volume parameters of the target and organs-at-risk (OAR) over a course of prostate radiotherapy using daily endorectal balloon and cone beam CT surveillance.  No changes in rectal volume were noted, which was attributed to daily ERB use.  Rectal DVH V40 and V60 were not statistically significant in difference between the original plans and CBCT-based plans.

Rectal Dose Sparing and DVH improvement

In addition to providing a favorable, reproducible anatomy for treatment, the use of an ERB has been shown to spare the rectum from unnecessary dosing (Patel et al, 2003).  Dr. Patel utilized conformal IMRT (with/without SV) with image guidance (BAT Ultrasound) along with a rectal balloon.  The rectal balloon in all cases resulted in a significant decrease in the absolute volume of rectal wall receiving greater then 60, 65, or 70 (note DVH findings in figure 5).  Specifically, the inflation of the rectal balloon results in a mean fractional high dose rectal sparing of 39%.  It is also likely that daily use of a rectal balloon, by reducing variability of rectal filling, will eliminate additional sources of dosimetric variability, creating more reliable dose volume vs. rectal toxicity data sets than are currently available.  The use of pretreatment ultrasound localization (IGRT) should only further enhance the confidence that such data sets reflect delivered rather than planned doses.  Patel et al. (2003) and Watcher et al (2002) showed similar results in DVH improvement when an ERB was used during RT.

Van Lin et al. (2007) evaluated rectal mucosal changes after prostate radiotherapy with an endorectal balloon.  Patients were assigned a Telangiectasia (T-score) to show how much radiation exposure was given to the rectum.  Findings were confirmed during rectosigmoidoscopy at 3 month, 6 month, 1 year, and 2 years after completion of the radiation treatment.  The study showed that ERB use reduced the dose to the posterior and lateral Rwall mucosa, while maintaining a high dose to the anterior mucosa.  This resulted in significant reduction of T 2-3 after 1 and 2 years and attributed to a reduced late rectal toxicity in the ERB Group (figure 5, 6).  Because a lower dose is delivered to the rectal wall, the changes to the rectal mucosa associated with radiation therapy are greatly reduced, resulting in fewer long-term side effects (van Lin et al, 2005 and van Lin et al, 2007).  Van Lin et al concluded that a patient friendly, single use device, is optimal and daily ERB position verification is mandatory (IGRT).  

D’Amico et al. (2006) found similar results in reduced rectal toxicity with the use of an ERB.  In the study, the volume of the rectum exceeding 70 Gy was very small, measuring only 3.7cm on average when the ERB was used.  No grade 3 rectal bleeding events were observed for men followed for a minimum of 1 year.

Dose Escalation

Delivering higher than standard doses to aggressive prostate cancer has been shown to improve failure free survival (Pollack et al, 2002 and Zietman et al, 2004).  However, increasing the dose to the target also places the anterior rectal wall at risk for the late effect of radiation proctopathy.  Because ERB is also effective at removing the rectum from the treatment area, D’Amico et al (2006) has shown that use of an ERB during treatment allows the dose delivered to the target to be escalated with no significant proctopathy while also greatly increasing the rates of local control.  He also demonstrated patients receiving > 70 Gy to more than 25% of the rectum had a 5-year risk of grade 2-3 complications of 37% compared to a risk of 13% if < 25% of the rectum received the dose.

Safety and Tolerability

Safety and tolerability of various rectal balloon devices have been well documented in large clinical studies.  Teh et al demonstrated that the ERB device is well tolerated by 396 patients (over 4 years) with 99.2% tolerating the device at 100cc’s over the entire treatment period.  

Ronson et al. collected a retrospective analysis of 3,561 patients who underwent conformal radiation for prostate cancer in which a rectal balloon was used.  Of all the patients evaluated, 3,474 (97.6%) tolerated the balloon throughout treatment and the study concluded that intrarectal balloons are well tolerated over a full course of conformal prostate irradiation.  

With the proper design, the balloon also provides a tool for physicians to use with patients in which the bowel is dropping into the treatment margin (low lying bowel).  Often these patients are deemed untreatable due to this anatomical constraint.

SV Variation

Studies have shown that seminal vesicle motion variation may be even more considerable than prostate motion.  Margins must be large enough to avoid any geographic miss while still accounting for patient setup variations and internal organ movement during RT delivery.  Frank et al. (2008) used a specially designed CT based linear accelerator (CT on rails) to analyze the effect of rectal and bladder volume changes on the SV position during RT.  The study found the variability in SV displacement to be much larger then that of the prostate suggesting that a greater margin is needed for the SV (as larger as 20mm).  In addition, displacement during treatment correlated with the rectal volume changes in 93% of daily scans, which shows that controlling the rectal volume is vital when the SV are treated.  Aherne et al. (2009 ASTRO Abstract) investigated SV interfraction motion and SV CTV coverage when matching to prostate FM in order to determine the impact of this motion on image guidance strategies.  Nine patients were treated with a fiducial marker inserted into each SV then imaged daily using electronic portal imaging and weekly kvCT.  The study concluded that a 5 mm margin was required in 56.17% of the fractions, and an expansion of 10 mm was required in 95.5% of all fractions.  The study implies that some protocols may result in sub-therapeutic doses of radiotherapy to the SV thus requiring a larger SV PTV expansion.

A rectal balloon with the proper symmetry and length should have the ability to immobilize the seminal vesicles along with the prostate.  Watcher et al (2002) reported a rectal balloons ability to increase the distance between seminal vesicles and posterior rectum wall in some patients, while having the adverse effect in other patients.  This finding was more then likely attributed to specific patients where certain anatomical characteristics (large bladder) have as much of an impact on SV position as the presence of a balloon.  In addition, the entire rectum was defined in their study as wall plus contents (including the balloon).  Patel et al. (2003) reported a benefit for all of the generated types of treatment plans regardless of whether the SV were included in the PTV.  Ho Cho et al (2009) studied the reproducibility of a properly designed rectal balloon (correct symmetry, depth markers) by using repeated CT scans with an ICC model and found that the balloon (with the tip placed inside the balloon) had the ability to “immobilize” the SV as well as the prostate.  Conformal IMRT techniques can thus be applied to the SV while accounting for the immobilization of the organs (SV) during RT with the use of a properly designed balloon.

Summary

In summary, while IGRT allows the physician to track the prostate motion, it does so only during a specific snapshot in time.  This creates a continual “chasing the anatomy” scenario.  The endorectal balloon offers true minimization of the motion and movement of the prostate and seminal vesicles, as well as displacement of the healthy tissue away from the treatment margins through simple geometry.  

Furthermore, the endorectal balloon controls the actual prostatic rectal interface by creating a fixed rectal volume throughout therapy, while solving the immobilization and organ variation problem.

Other advantages attributed to the device include: reduction of dose to the rectum, reduction in margin surrounding the prostate, displacement of low lying bowel, reduction of dose related side effects, and the ability to escalate dose and increase the rate of local tumor control of prostate cancer.

Works Cited

Aherne, N. J. et al (2009). 2259 Daily fiducial based tracking of seminal vesicle motion in image guided dose escalated IMRT: Are we kidding ourselves regarding seminal vesicle coverage? Proceeding of the 51rst Annual ASTRO Meeting , S297.

Pollack, A., et al (2002). Prostate biopsy status and PSA Nadir level as early surrogates for treatment failure: Anlaysis of a prostate cancer randomized radiation dose escalation trial. Int. J. Radiation Oncology Bio. Phys. , 54 (3), 677-685.

Teh, B., et al (2002). The use of rectal balloon during the delivery of intensity modulated radiotherapy (IMRT) for prostate cancer: More than just a prostate gland immobilization device? Cancer J. , 8 (6), 476-83.

Ronson, B., et al (2006). Patient Tolerance of Rectal Balloons In Conformal Radiation Treatment of Prostate Cancer. Int. J. Radiation Oncology Biol. Phys. , 64 (5), 1367-1370.

Beard, C.J., et al (1996). Analysis of prostate and seminal vesicle motion: Implications for treatment planning. Int. J. Radiation Oncology Biol. Phys. , 34 (2).

D'Amico, A.V., et al (2001). A practical method to achieve prostate gland immobilization and tyarget verification for daily treatment. Int. J. Radiation Oncology Biol. Phys. , 51 (5), 1431-1436.

D'Amico, A.V., et al (2006). A prospective evaluation of rectal bleeding after dose-escalated three-dimensional conformal radiation therapy using an intrarectal balloon for prostate gland localization and immobilization. Adult Urology , 67, 780-784.

Little, D, et al (2003). Use of portal images and Bat Ultrasonography to measure setup error and organ motion for prostate IMRT: Implications for treatment margins. Int. J. Radiation Oncology Biol. Phys. , 56 (5), 1218-1224.

Van Lin, E.  et al (2007). Reduced late rectal mucosal changes after prostate three-dimensional conformal radiotherapy with endorectal balloon as observed in repeated endoscopy. Int. J. Radiation Oncology Bio. Phys. , 67 (3), 799-811.

Ogino, I., et al (2008). Reducation of Prostate motion by removal of gas in rectum during radiotherapy. Int. J. Radiation Oncology Bio. Phys. , 72 (2), 456-466.

Ho Cho, J., et al (2009). Positional reproducibility and effects of a rectal balloon in prostate cancer radiotherapy. J Korean Med Sci , 24, 894-903.

Langen, K., et al (2008). Observations on real-time prostate gland motion using electromagnetic tracking. Int. J. Radiation Oncology Bio. Phys. , 71 (4), 1084-1090.

Bastasch, M., et al (2006). Tolerance of Endorectal Balloon in 396 Patients Treated With Intensity-Modulated Radiation Therapy (IMRT) for Prostate Cancer. American Journal of clinical Oncology , 29 (1), 8-11.
Patel, R., et al (2003). Rectal dose sparing with a balloon catheter and ultrasound localization in conformal radiation therapy for prostate cancer. Radiotherapy and Oncology , 67, 285-294.

Crevoisier, R., et al (2005). Increased risk of biochemical and local failure in patients with distended rectum on the planning CT for prostate cancer radiotherapy. 62 (4), 965-973.

Wachter, S., et al (2002). The influence of a rectal balloon tube as internal immobilization device on variations of volumes and dose-volume histograms during treatment course of conformal radiotherapy for prostate cancer. Int. J. Radiation Oncology Bio. Phys. , 52 (1), 91-100.

Frank, S., et al (2008). Quantification of prostate and seminal vesicle interfraction variation during IMRT. Int. J. Radiatioin Oncology Bio. Phys. , 71 (3), 813-820.

Vapiwala, N., et al (2009). 2341 Is what you see really what you get? Quantification of discrepancies between planned vs. delivered dose during prostate radiotherapy using daily endorectal balloon and cone beam CT surveillance. Proceedings of the 51rst Annual ASTRO Meeting , S335.

McGary, J. E., et al (2002). Prostate Immobilization using a rectal balloon. Journal of Applied Clinical Medical Phyics , 3 (1), 6-11.