Commentary (Sylvester): Integrating Hormonal Therapy With External-Beam Radiation and Brachytherapy for Prostate Cancer

Drs. Andrews and Roach present an excellent review and discussion of the existing literature regarding the role of androgen ablation therapy in patients being treated with external-beam radiation therapy (EBRT) and prostate brachytherapy. However, the indications for, and optimal timing of androgen ablation with radiation therapy remain controversial, particularly in regard to brachytherapy. The authors highlight several important concepts including ways in which large randomized trials give insight into the integration of androgen ablation with EBRT in patients with high-risk disease. Patients with high-Gleason-score prostate cancer treated on RTOG 85-31 experienced improved overall and metastatic disease- free survival when long-term adjuvant androgen ablation was added to low-dose EBRT.[1] These patients were at increased risk for micrometastatic disease at time of treatment. Long-duration adjuvant androgen ablation (similar to several years of adjuvant hormonal therapy in women with breast cancer) resulted in improved outcomes. Short-course neoadjuvant and concurrent hormonal therapy in RTOG 86-10 and in RTOG 94-13 demonstrate improved local control rates and biochemical relapse-free survivals when combined with low-dose EBRT in patients with high-risk disease.[2,3] This argument is further supported by the improvement in overall survival noted with neoadjuvant/concurrent hormonal therapy plus low-dose EBRT in the recently reported randomized trial by D'Amico.[4] Drs. Andrews and Roach nicely clarify how to integrate androgen ablation with EBRT. Complications in Data Interpretation
Importantly, they discuss the under-recognized fact that not all intermediate- risk or high-risk patients are alike. In general, the intermediate- and high-risk patients in the surgical literature have more favorable characteristics than the intermediateand high-risk patients in the brachytherapy literature, who in turn have more favorable qualities than those treated in the large randomized RTOG EBRT trials.[5] This clearly complicates efforts to interpret results from various studies and extrapolate these interpretations into treatment recommendations for current patients. Using the RTOG data to stratify patients into "RTOG low-risk" patients who do not benefit from androgen ablation use, "RTOG intermediate- risk" patients who benefit from short-term androgen ablation use, and "RTOG high-risk" patients who benefit from long-term androgen ablation use is attractive in its simplicity and because the data are based on thousands of patients treated in phase III randomized trials. Patients with a low likelihood of local or distant failure (RTOG low-risk patients) will not benefit from the addition of androgen ablation. Those at a significant risk of locoregional failure (RTOG intermediate-risk patients) may benefit from short-course androgen ablation. Those at a significant risk of distant micrometastatic disease (RTOG high-risk patients) may benefit from long-term androgen ablation. In patients receiving prostate brachytherapy, the risk of local failure is exceptionally low (as long as high-quality implant procedures are performed), so for androgen ablation to be beneficial when added to brachytherapy (with or without EBRT) it should have a regional and/or distant effect. Theoretically, long-term androgen ablation combined with EBRT plus seeds may benefit very-high-risk patients, but short courses of androgen ablation with prostate brachytherapy, with or without EBRT, would not be expected to be beneficial unless the implant quality is suboptimal or unless other interactions are occurring (as suggested by the results of neoadjuvant/concurrent hormonal therapy plus whole-pelvis EBRT in RTOG 94-13). Inconclusive Findings
One major related concern is that the use of EBRT data to guide treatment decisions in brachytherapy patients is based on extrapolation. The data in the brachytherapy literature is largely negative. The study by Lee at al discussed in this review is interesting, but in that study, patients with high-quality implants did not benefit from androgen ablation and those who received androgen ablation were more recently treated patients who therefore had higher-quality implants. Those receiving androgen ablation and brachytherapy had a 36-month mean follow-up, whereas those treated with brachytherapy alone had a 63-month mean follow-up. These differences in implant quality and follow-up make these data inconclusive at best. The addition of androgen ablation to brachytherapy with or without EBRT has failed to improve outcomes in the reported experiences from the Seattle investigators, from Dattoli et al, and most others. In fact, a recent report of the pooled results of EBRT plus temporary high-dose-rate (HDR) prostate brachytherapy from William Beaumont, the Seattle Prostate Institute, and Kiel et al contained a significant proportion of patients who also received androgen ablation. They actually noted a worse cause-specific survival in "high-risk" patients who received EBRT, HDR brachytherapy, and androgen ablation compared to those who did not receive the androgen ablation (97% and 90%, respectively, P = .002).[6] None of the current brachytherapy studies in the literature discussing the role of androgen ablation are randomized. The studies of brachytherapy plus EBRT with or without androgen ablation did not routinely use wholepelvic EBRT during the EBRT portion of therapy, nor did they use long-term androgen ablation. Unfortunately, they all have significant limitations and neither prove nor disprove any advantage or disadvantage regarding the addition of androgen ablation to prostate brachytherapy with or without EBRT. Extrapolation From RTOG Data
Extrapolation of the RTOG 94-13 data is one of the most intriguing aspects of this review article. One cannot ignore the fact that this was a large phase III randomized trial involving prostate-specific antigen era patients.[ 3] The favorable interaction of whole-pelvic EBRT with neoadjuvant/ concurrent hormonal therapy in this trial suggests that short-course androgen ablation may have benefits beyond simply improving local control. Thus, the authors' proposal-to extrapolate from RTOG 94-13 and consider the addition of neoadjuvant/ concurrent hormonal therapy to whole-pelvic EBRT in those "RTOGlike" intermediate-risk patients receiving prostate brachytherapy plus EBRT-seems logical. So does the idea of even longer-duration androgen ablation adjuvantly in even higher- risk patients receiving EBRT plus brachytherapy. However, because this is extrapolation from EBRT data, because the current brachytherapy literature fails to show benefit for the addition of androgen ablation, and because there are significant toxicities associated with androgen ablation (primarily in long-term androgen ablation use), a randomized trial is clearly indicated. As for low- and intermediate-risk "brachytherapy" patients, the main role of androgen ablation is to shrink the prostate in those with glands that are too large to implant at time of presentation. One should also note that even the role of EBRT is undetermined in "brachytherapy intermediate-risk" patients and is currently being evaluated in an open RTOG trial.

Disclosures:

Dr. Sylvester is part owner of Pro-Qura, a quality assurance firm. In addition, various seed manufacturers (Oncura, Theragenics, Bard, Best) are vendors for his Seattle brachytherapy training course.

References:

1. Pilepich MV, Caplan R, Byhardt RW, et al: Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate with definitive radiotherapy: Report of Radiation Oncology Group protocol 85-31. J Clin Oncol 15:1013, 1997.
2. Pilepich MV, Winter K, John MJ, et al: Phase III Radiation Therapy Oncology Trial 86- 10 of androgen deprivation before and during radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 50:1243, 2001.
3. Roach M, DeSilvio ML, Lawton C, et al: Phase III trial comparing whole pelvic versus prostate only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 94- 13. J Clin Oncol 21:1904-1911, 2003.
4. D’Amico AV, Manola J, Loffredo M, et al: 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer. JAMA 292:821-827, 2004.
5. Sylvester JE, Blasko JC, Grimm PG, et al: Ten-year biochemical relapse-free survival after external beam radiation and brachytherapy for localized prostate cancer: The Seattle experience. Int J Radiat Oncol Biol Phys 57:944- 952, 2003.
6. Galalae RM, Martinez A, Mate T, et al: Long-term outcome by risk factors using conformal high-dose-rate brachytherapy (HDRBT) boost with or without neoadjuvant androgen suppression for localized prostate cancer. Int J Radiat Oncol Biol Phys 58:1048-1055, 2004.