Clinical investigation: prostate
Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer

Presented at the 42nd ASTRO meeting in Boston, MA, November 2000.
https://doi.org/10.1016/S0360-3016(02)02733-5Get rights and content

Abstract

Purpose: To overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed.

Methods and Materials: Between November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50–11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level ≥10.0 ng/mL, Gleason score ≥7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose <93 Gy (58 patients) and high-dose biologically effective dose >93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure.

Results: The median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p <0.001). Improvement occurred in the cause-specific survival in favor of the brachytherapy high-dose level (p = 0.014). On multivariate analysis, a low-dose level, higher Gleason score, and higher nadir value were associated with increased biochemical failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%.

Conclusion: Pelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause-specific survival with higher doses. These results, coupled with the low risk of complications, the advantage of not being radioactive after implantation, and the real-time interactive planning, define a new standard for treatment.

Introduction

External beam radiotherapy (EBRT) has been the reference standard treatment for patients with unfavorable prostate cancer, but the results have been suboptimal. The 5- and 10-year survival rates, ranging from 40% to 75% and 35% to 55%, respectively, are discouraging 1, 2, 3, 4. In addition, patients with posttreatment persistence of the disease in the gland have been found to have an increased risk of symptomatic local failure and distant metastasis and a decrease in overall survival 5, 6, 7, 8. From the above information, one may conclude that an improvement in local control may have an impact on biochemical control (BC), disease-free survival, and cause-specific survival. Consequently, therapeutic efforts are now concentrated toward this goal. The strategies tested to improve local control in the past decade have included hormonal ablation before, during, and after standard RT 9, 10, 11; particle beam therapy with either protons or neutrons as a boost to EBRT 12, 13; a permanent seed low-dose-rate (LDR) implant as a boost to EBRT 14, 15; and dose-escalating conformal RT using one of the following two pathways: three-dimensional conformal RT (3D-CRT) 16, 17 or conformal high-dose-rate (HDR) brachytherapy 18, 19. Tumor dose escalation should hypothetically overcome the radioresistance of tumor clonogens seen at conventional dose levels. The question remains as to which of these two strategies best escalates the dose sufficiently to obtain a greater therapeutic gain.

With standard EBRT fields and traditional treatment planning, the true extent of the target volume may not receive the prescribed dose. Hence, the relatively low dose delivered to the tumor is the most likely explanation for the suboptimal results. In this setting, perhaps the benefit of adding hormonal treatment 9, 10, 11 relates to a local effect on the malignant cells (fixation of potentially lethal damage) such that cell death from adding hormonal therapy would be equivalent to having delivered an additional dose of radiation. Although with 3D-CRT, the target volume and surrounding normal structures are better delineated, resulting in planning the delivery of a higher dose, dose escalation may not always be safe or possible. This is the case for patients with geometrically unfavorable lesions, which may be undertreated. In addition, other drawbacks to this approach include the accuracy of target volume definition and uncertainties related to daily dose delivery. Systematic and random setup errors, internal organ motion, deformation, and organ changes related to treatment have been well documented and may limit the efficacy of 3D-CRT 20, 21, 22, 23. At William Beaumont Hospital, we have developed a strategy, the adaptive radiotherapy process, which has been tested to overcome motion uncertainties 24, 25, 26.

As a result of the potential drawbacks of 3D-CRT, in 1991, we began the first sequential dose escalating, prospective clinical trial using transrectal ultrasound (TRUS)-guided conformal HDR brachytherapy as a means of delivering the boost dose 18, 19, 27, 28. The TRUS-guided transperineal implant technique allows direct and continuous visualization of the relationship between the rectal wall, urethra, bladder, and prostate contour 18, 19, 28, 29. Our interactive real-time optimization program “the HDR smart seed technique,” selects the needle positions, allowing us to correlate intraoperatively the anatomic relationship of the organs with the needle placement and their spatial distribution 27, 28, 29.

To address the issues of target volume definition and uncertainties of dose delivery systems, we prospectively performed and reported our study on overcoming internal prostatic motion and setup inaccuracies with conformal image-guided interstitial HDR brachytherapy (30). We documented and quantified intraoperatively the magnitude of prostatic motion and distortion that takes place in all three dimensions during the implant procedure, as well as the movement of the prostate gland between two separate implant procedures. We demonstrated no shifting or displacement of the location of the prostate just before treatment (planning volume) to that of the position of the gland immediately after treatment was delivered (treated volume) (30). Consequently, the prescribed dose and delivered dose were the same.

From the patient and family perspective, a great advantage of HDR brachytherapy over LDR permanent seed prostate brachytherapy is that once the HDR dose is delivered, the patient is no longer radioactive. This approach avoids all the radiation safety and protection issues related to permanent seed implantation. From the healthcare payers perspective, a decrease in cost results because the permanent seeds do not have to be purchased for each patient.

The key to the delivery of conformal HDR prostate brachytherapy was the development of an interactive real-time dose-optimization program in 1991 at William Beaumont Hospital (27). We termed this program “the HDR smart seed technique.” This optimization program allows (1) real-time, computer selection of ideal needle location and determination of actual needle position, (2) direct visualization of isodose curves in relationship to real-time prostate gland boundaries, (3) determination of actual dose at multiple prostate levels with corresponding doses to the rectal wall and urethra, (4) detection and compensation for prostate motion during the procedure (30), (5) intraoperative dose volume analysis, and (6) intraoperative analysis of implant quality 18, 19, 28, 29, 30, 31, 32, 33.

The William Beaumont Hospital HDR prostate brachytherapy boost trial is the first prospective dose-escalation brachytherapy trial ever performed. The study was undertaken to test the hypothesis that local failure for patients with prostate cancer harboring large-volume disease is related to both large cell mass and radioresistant cell clones, which require biologically higher radiation doses than conventionally delivered with EBRT. We report the results to date of this trial.

Section snippets

Methods and materials

Between November 1991 and August 2000, 311 patients with unfavorable and/or large-volume prostatic adenocarcinoma were prospectively enrolled into this dose-escalating trial. They were treated with pelvic EBRT interdigitated with a conformal HDR (C-HDR) brachytherapy boost at William Beaumont Hospital (Royal Oak, MI). Sequentially seen patients meeting the study criteria and with an expected survival of >5 years were offered participation in this dose-escalating trial. All patients signed an

Results

The clinicopathologic characteristics, including stage, Gleason score, pretreatment PSA, and age by brachytherapy dose level are listed in Table 2. According to the AJCC-93, Stages T1c-T2a were seen in 30%, T2b in 28%, T2c in 32%, and T3 in 10% (70% of these patients had bulky disease ≥T2b). Of the 207 patients, 35 patients had all 3 poor prognostic factors (pretreatment PSA ≥10 ng/mL, Gleason score ≥7, and clinical Stage T2b or higher), leaving 75 patients with 2 poor factors; the remaining

Discussion

The optimal treatment for patients with unfavorable prostate cancer remains undefined. During the past decade, several strategies directed to overcome radioresistance and/or large cell mass have been tested for tolerance and possible beneficial outcome. They include the addition of hormonal ablation before standard EBRT 9, 10, 11, EBRT with a particle beam boost 12, 13, EBRT with a LDR permanent seed boost 14, 15, 3D-conformal EBRT 16, 17, and conformal HDR brachytherapy combined with EBRT 31,

Conclusion

Pelvic EBRT interdigitated with TRUS-guided real-time conformal HDR brachytherapy boost is both a precise dose delivery system and an effective treatment modality for patients with large-volume prostate cancer. An incremental beneficial effect on BC and, most importantly, in cause-specific survival according to the brachytherapy dose level was demonstrated in this report. When coupled with the advantage that the patient is not radioactive after brachytherapy and the low risk of complications,

Acknowledgements

The authors thank Michelle Wallace, R.N., B.S.N. and Maria Hardy, R.N., M.S.N., for their assistance in data management. We also thank the members of the Departments of Urology and Radiation Oncology who enrolled patients in the study and cared for them.

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