Permanent prostate brachytherapy with or without supplemental therapies is a highly effective treatment for clinically localized prostate cancer, with biochemical outcomes and morbidity profiles comparing favorably with competing local modalities. However, the absence of prospective randomized brachytherapy trials evaluating the role of supplemental external-beam radiation therapy (XRT) has precluded the development of evidence-based treatment algorithms for the appropriate inclusion of such treatment. Some groups advocate supplemental XRT for all patients, but the usefulness of this technology remains largely unproven and has been questioned by recent reports of favorable biochemical outcomes following brachytherapy used alone in patients at higher risk. Given that brachytherapy can be used at high intraprostatic doses and can obtain generous periprostatic treatment margins, the use of supplemental XRT may be relegated to patients with a high risk of seminal vesicle and/or pelvic lymph node involvement. Although morbidity following brachytherapy has been acceptable, supplemental XRT has shown an adverse impact on long-term quality of life. The completion of ongoing prospective randomized trials will help define the role of XRT as a supplement to permanent prostate brachytherapy.
Merrick, Wallner, Butler, and Blasko have provided a timely and well articulated review on the proper use of supplemental external-beam radiation therapy in men treated with permanent prostate brachytherapy. These authors have contributed much to the prostate brachytherapy literature, and their opinions carry significant weight in this arena.
As the authors state, the reasons to add supplemental external-beam radiation therapy are to enhance the periprostatic dose, to escalate the intraprostatic dose, to rectify technically inadequate implants, and to treat the seminal vesicles and/or pelvic lymph nodes in their entirety. The authors then consider each of these issues by presenting retrospective data that suggest supplemental external-beam radiation is unnecessary.
External-Beam Radiation Reconsidered
The distilled version of their argument is that (1) extraprostatic seed placement provides enough dose laterally to treat extraprostatic extension adequately; (2) intraprostatic doses achieved with brachytherapy alone are high enough; (3) external-beam radiation therapy shouldn’t be needed to "spackle" a poor implant, because improved computer-based treatment planning using wide margins, attention to detail, and intraoperative dosimetry should prevent such incidents, and (4) if good technique is applied, only patients at high risk of pelvic node or high seminal vesicle involvement will need supplemental external-beam radiation therapy.
In summary, the authors’ opinion is that supplemental external-beam radiation therapy is not required in men who receive a technically adequate implant if the risk of pelvic lymph node or seminal vesicle involvement is low. Is this opinion supported by level 1 evidence? The authors’ answer is yes; we believe that the answer is not yet. In arguing this position, we will emphasize two concepts that are important for the design and interpretation of clinical trials: power and generalizability.
Key Clinical Trials
To our knowledge, three randomized trials have included brachytherapy in each arm, and Merrick and coinvestigators have been responsible for two of these. We commend the authors for designing, completing, and reporting studies that will be important contributions to the literature when the follow-up is mature. Still, the question at the heart of these two trials is, how important is external-beam radiation therapy in men treated with prostate brachytherapy?
The first trial, outlined in the authors’ Figure 7, was designed by the Seattle/Wheeling consortium, and the target accrual was 600 patients. The first published report from this study included information on only 159 analyzable patients (27% of the study population), with a median follow-up of less than 3 years. At the time of this publication, only 21 patients have developed a biochemical failure (12 in the 20-Gy arm, 9 in the 44-Gy arm).
The authors used these results to support their conclusion that supplemental external-beam radiation therapy is unnecessary. It is our contention that this conclusion is premature and is based on a preliminary report with insufficient follow-up. In short, the published study is underpowered to draw meaningful conclusions. A simple power analysis indicates that the likelihood of finding a difference of the same magnitude that the authors hypothesized at the beginning of the study is approximately 20%. In other words, it is very possible that a clinically important difference between the treatment arms has not been observed because the study is, as yet, underpowered.
The authors are now randomizing similar patients to a 20 vs 0 Gy external-beam radiation therapy trial. These two consecutive randomized, controlled trials will likely be combined by the authors to infer the value of supplemental external-beam radiation therapy. It should be emphasized that these studies are not designed as noninferiority trials. The sample size in each case is chosen to have the power to show differences between the arms. If the log-rank comparison on mature data is greater than 0.05, it is likely that smaller differences exist. In this setting, a "negative" study should not be interpreted as equivalence between the arms. In other words, the transitive property should not be used to suggest that if 20 Gy is no worse than 40 Gy and 0 Gy is no worse than 20 Gy, then 0 Gy must be no worse than 40 Gy. Clinical trial interpretation should not work that way.
The second concern regarding the Seattle/Wheeling studies is the generalizability of the findings. All patients enrolled receive their implants from one of two highly skilled and very experienced brachytherapists, each of whom has had more than a decade of experience. The authors use a well described technique of periprostatic seed placement that is not universally practiced. It is not clear if any inferences drawn from these studies are appropriate to other clinicians with less experience using different techniques.
The authors mention the largest study yet designed to examine the value of supplemental external-beam radiation therapy in men treated with prostate brachytherapy-the Radiation Therapy Oncology Group (RTOG) 0232 trial, led by primary investigator Bradley Prestidge of the Texas Cancer Clinic, San Antonio. This study is randomizing selected patients with intermediate-risk disease to receive brachytherapy alone or with 45 Gy of external-beam radiation. The target accrual for this study is 1,520 patients, and the primary end point is overall survival. This sample size will be sufficient to detect a hazard ratio of 1.3 on the primary end point with 90% power. The study will include patients from more than 30 institutions, making the result much more generalizable to the radiation oncology community as a whole. Until this study is completed and appropriate follow-up time has passed, however, the role of supplemental external-beam radiation therapy will remain unclear.
In conclusion, Merrick and colleagues have provided an excellent review of the data supporting their contention that only patients with a high risk of pelvic lymph node or seminal vesicle involvement should receive supplemental external-beam radiation therapy. The reasons to add such treatment make intuitive sense, but its role must be determined through appropriately designed randomized, controlled trials with mature follow-up. We strongly encourage clinicians to consider enrolling patients in RTOG 0232, a trial that should settle this important issue once and for all.
-Michael A. Papagikos, MD
-W. Robert Lee, MD, MS
Dr. Lee is a consultant for Oncura.
1. Wallner K, Merrick G, True L, et al: 20 Gy versus 44 Gy supplemental beam radiation with Pd-103 prostate brachytherapy: Early biochemical outcomes from a prospective randomized multi-center trial. Radiother Oncol 75:307-310, 2005.