Clinical Investigation
Human Collagen Injections to Reduce Rectal Dose During Radiotherapy

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Objectives

The continuing search for interventions, which address the incidence and grade of rectal toxicities associated with radiation treatment of prostate cancer, is a major concern. We are reporting an investigational trial using human collagen to increase the distance between the prostate and anterior rectal wall, thereby decreasing the radiation dose to the rectum.

Methods

This is a pilot study evaluating the use of human collagen as a displacing agent for the rectal wall injected before starting a course of intensity-modulated radiotherapy (IMRT) for prostate cancer. Using a transperineal approach, 20 mL of human collagen was injected into the perirectal space in an outpatient setting. Computerized IMRT plans were performed pre- and postcollagen injection, and after a patient completed their radiotherapy, to determine radiation dose reduction to the rectum associated with the collagen injection. Computed tomography scans were performed 6 months and 12 months after completing their radiotherapy to evaluate absorption rate of the collagen. All patients were treated with IMRT to a dose of 75.6 Gy to the prostate.

Results

Eleven patients were enrolled into the study. The injection of human collagen in the outpatient setting was well tolerated. The mean separation between the prostate and anterior rectum was 12.7 mm. The mean reduction in dose to the anterior rectal wall was 50%. All men denied any rectal symptoms during the study.

Conclusions

The transperineal injection of human collagen for the purpose of tissue displacement is well tolerated in the outpatient setting. The increased separation between the prostate and rectum resulted in a significant decrease in radiation dose to the rectum while receiving IMRT and was associated with no rectal toxicities.

Introduction

In the United States, more than 180,000 men will be diagnosed with prostate cancer each year (1). Interventional treatment options include: observation, surgical removal (prostatectomy), freezing/cryosurgery, hormonal therapy, prostate seed implant, or conformal radiation. Approximately 30% will choose interstitial implant therapy, 30% of the men will choose surgery, and 30% will choose external beam radiotherapy (2). A minority will choose observation or other forms of treatment for their prostate cancer.

The treatment modality providing the best outcome is still debatable. However, the side effects have become less toxic and less profound with implant therapy and three-dimensional (3D) conformal radiotherapy. Advancements in treatment positioning and target localization have significantly improved the outcome and diminished the side effects (3). Since the inception of conformal 3D radiotherapy, technology has evolved into intensity-modulated radiotherapy (IMRT), a delivery technique in which physicians have focused considerable attention to the delivered dose toward the target and surrounding tissues. Investigators have been able to correlate side effects to the amount of tissue receiving a certain radiation dose measured in terms of dose–volume histogram 3, 4, 5.

Striving for further improvement, investigators are attempting to decrease the dose to the anterior rectal wall and thereby decrease the potential for radiation-induced side effects. For conformal radiotherapy, it is preferred that the rectum receive less than 40% of the prescribed treatment dose in hopes of minimizing the radiation induced side effects 3, 4, 5. Traditionally, a radiation oncologist is trained using three principles to minimize the delivered dose: time, distance, and shielding 6, 7. The less time an area is exposed to radiation, the lower the dose there is from exposure. The greater the distance from the radiation source, the lower the dose delivered. Finally, more shielding or techniques to enhance the conformality of treatment delivery to the treatment target will also decrease the delivered dose 6, 7.

Identifying a technique to decrease the radiation dose to the rectum during radiotherapy for prostate cancer is desirable. One technique for decreasing the amount of radiation received by the anterior rectal wall is to insert an inflatable balloon applicator into the rectum on a daily basis 3, 4. The premise is that more of the rectum is displaced away from the prostate than the small portion of rectum that is pushed toward the prostate. Therefore a smaller amount of rectum is receiving radiation and consequently the side effects from radiation should be diminished 3, 4. Unfortunately, there is daily variation with the balloon technique that leads to an uncertainty with the intended dose delivered to the prostate and uncertainty in dose reduction to the rectum. This study examines an investigational technique that allows the total rectum to be displaced away from the prostate during course of radiotherapy, thus limiting the dose to the rectum and therefore decreasing the risk of radiation induced side effects.

In a US rural community outpatient setting, all prostate patients electing IMRT were offered enrollment in this Institution Review Board–approved pilot study. Between August 2002 and August 2003, 11 men >45 years of age with Stage 2 or Stage 3 prostate cancer, prostate-specific antigen >4, and Gleason scores of 6–10 elected to participate. Seven men had Stage 2 cancer and 4 men had Stage 3 cancer. No patients had involvement of their seminal vesicles or lymph nodes. Three of the men had a Gleason score of 6; 7 had a Gleason score of 7, with 1 patient having a Gleason score of 8.

Section snippets

Methods and Materials

The technique evaluated consisted of injecting a displacing agent between the radiation target and the adjacent sensitive tissues. The displacing agent used was required to include properties such as its ability to maintain its natural properties during and after exposure to radiation, and to remain in its location until after a treatment course has concluded. Ideally, the displacing agent would be instilled once before treatment and would not require additional agents, repositioning, or

Results

Each patient who elected to proceed with the ongoing protocol tolerated the collagen injection well. No one reported symptoms suggestive of an allergic reaction. Three patients reported a sensation similar to a light rectal pressure that resolved 3–4 h after the injection. One patient experienced urinary retention and required placement of a Foley catheter. The catheter was removed 3 days after the injection without difficulty or recurrence. This instance of urinary retention was presumed

Discussion

The modern era has witnessed the evolution of radical prostatectomy, external beam radiotherapy, and interstitial permanent seed brachytherapy to a point where the results are nearly equivalent 3, 4. Although some authors may debate that their techniques have achieved superior results, by and large the results have been too close to claim that one modality is definitely superior to the other. If this is so, then the decision for therapy must consider treatment related side effects and quality

Acknowledgments

The authors would like to thank Life Cell Corporation (Branchburg, NJ) for supplying Cymetra for this trial and Ms. Lynne Berg for her assistance with treatment planning and Ms. Nancy Cronquist for her assistance with nursing assessments.

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Conflict of Interest: none.

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