Androgen deprivation therapy (ADT) has been used in the management of prostate cancer for more than four decades. Initially, hormone therapy was given largely for palliation of symptomatic metastases. Following several randomized trials of patients with intermediate- to high-risk prostate cancer that demonstrated improvements in biochemical control and survival with the addition of ADT to external beam radiotherapy, there was a dramatic increase in the use of hormone therapy in the definitive setting. More recently, the safety of ADT has been questioned, as some studies have suggested an association of hormone therapy with increased cardiovascular morbidity and mortality. This is particularly worrisome in light of practice patterns that show ADT use extrapolated to situations for which there has been no proven benefit. In the setting of dose escalation with modern radiotherapy, in conjunction with the latest concerns about cardiovascular morbidity with ADT, the magnitude of expected benefit along with potential risks of ADT use must be carefully considered for each patient.
Androgen Deprivation Therapy and Brachytherapy
The use of prostate seed brachytherapy has historically been reserved for patients with low- to intermediate-risk prostate cancer, as early outcomes of high-risk disease treated with brachytherapy were poor. However, this was prior to the era of rigorous dosimetric cut-points and coverage of periprostatic tissue. Numerous modern series from high-volume institutions have now demonstrated superior control rates with the use of brachytherapy.[23-25] One must bear in mind the more favorable disease profile of high-risk brachytherapy series compared with EBRT studies; in the largest series, average Gleason scores were 7 to 8 and PSA was 12–15 ng/mL.[24,26] ADT is commonly used prior to brachytherapy for the purpose of reducing prostate size to improve the technical feasibility and side effect profile of brachytherapy, but it is not routinely given to achieve better tumor control. There has been no randomized trial investigating the impact of ADT on outcomes in conjunction with brachytherapy, and thus we currently rely on retrospective series to guide management.
Merrick et al. reported on 204 high-risk patients treated with pelvic EBRT followed by brachytherapy; they found that men treated with ADT had a significant improvement in biochemical control, with 10-year biochemical progression-free survival of 80% in hormone-naive patients, compared with 90%–95% in patients who received ADT. This provides some evidence that even with ablative radiation dose to the prostate, there may still be benefit from ADT in patients with high-risk disease. There was no difference in cause-specific survival (CSS) or OS, although with long-term CSS rates greater than 90%, it would likely require a large sample size to detect a difference. A published series of intermediate- to high-risk patients treated at Mount Sinai Medical Center also showed improvement in biochemical control with the addition of neoadjuvant and adjuvant ADT; 5-year freedom from biochemical failure (FBF) for high-risk patients was 74% with ADT, vs a dismal 46% without it. There was no difference among all patients who received a good-quality implant, however, with a 5-year FBF of 80% with or without ADT, whereas in patients who received a low implant dose, the 5-year FBF was 79% vs 38% (P = .0037). Patients were not further subdivided based on disease risk to assess the impact of both dose and androgen suppression specifically in high-risk patients; however, in high-risk patients who received both ADT and a high-dose implant, the reported 4-year FBF was 77%. In multivariate analysis, ADT use was the most significant predictor of biochemical control in both the high-risk patients and low-dose group. A recent multicenter analysis investigating the impact of radiation dose noted a significant improvement in 5-year biochemical control with ADT, from 77.5% to 96% (P = .001) in patients who received high-dose implants. Longer follow-up is necessary to confirm these results and allow for restoration of testosterone levels.
There are conflicting data regarding use of ADT with brachytherapy, with some evidence of biochemical improvement in high-risk patients but no survival benefit; this further supports the theory that with adequate radiation dose, the benefit of ADT may be lost, although longer follow-up is needed. To help answer this question, there is an ongoing multi-institutional randomized trial investigating ADT with brachytherapy in high-risk patients; however, the trial may close early without results, as accrual is poor.
Androgen Deprivation Therapy and Radical Prostatectomy
Historically, radical prostatectomy (RP) has not been the treatment of choice for high-risk prostate cancer, primarily due to concerns regarding the ability to obtain clear margins in locally advanced disease. With the use of PSA and earlier detection, the contemporary cohort of high-risk patients consists less of those with bulky disease and more of patients with higher-grade tumors, making some patients appropriate candidates for surgery. At least 10 randomized trials have been performed investigating the role of ADT in conjunction with RP; however, most of these studies largely comprised of patients with early-stage disease. Some investigations showed improvement in pathologic findings, with reports of fewer positive margins, histologic down-grading, and decreased rates of lymph node involvement.[28-31] Despite improved pathologic outcomes, this did not consistently translate into any difference in disease control. No trials demonstrated an improvement in overall survival, with the exception of a study published by Messing et al. that randomized 98 pathologically node-positive patients to immediate vs deferred ADT after RP. Ten-year OS was 75% vs 50% (P = .04) and CSS was 85% vs 53% (P = .0004), favoring immediate ADT. It is noteworthy that patients in the delayed arm were not treated until development of clinically evident metastases.
ADT has been incorporated into the treatment regimen in numerous trials assessing the utility of chemotherapy as part of multimodality therapy for high-risk disease. Southwest Oncology Group performed a phase III study (S9921) comparing adjuvant ADT after RP with ADT plus six cycles of mitoxantrone and prednisone. TAX-3501 was a three-arm randomized trial comparing surveillance, adjuvant ADT, and adjuvant ADT plus docetaxel in high-risk patients. Both studies closed early due to poor accrual. CALGB 90203, an ongoing trial, is investigating neoadjuvant ADT with docetaxel vs RP alone. In summary, outside of node-positive disease, there are no data supporting the use of ADT in conjunction with RP.
Timing and Duration
Both American and European groups conducted trials comparing long-term and short-term ADT with EBRT after earlier studies showed benefit with long-term ADT. In RTOG 92-02, men with clinical T2c–T4 disease were randomized to 4 months of neoadjuvant and concurrent ADT or 2 years total of ADT. More than 50% of men had T3–4 disease and 33% had PSA > 30 ng/mL. There was a significant improvement in 10-year CSS and biochemical failure, but no difference in OS. An OS benefit was detected in a subset analysis of patients with Gleason scores of 8 to 10; the 10-year OS rate was 45% for long-term ADT vs 32% for short-term ADT (P = .006). EORTC 22961 compared 6 months vs 3 years of concurrent and adjuvant treatment, with the goal of showing noninferiority of shorter course ADT. Seventy-five percent of patients had T3–4 disease and median PSA was 19 ng/mL. After median follow-up of 6 years, patients who remained on ADT for 3 years had statistically significantly improved OS, CSS, and biochemical control. Thus, the existing data suggest that very-high-risk, locally advanced patients seen more commonly in an earlier era, long-term ADT of 2–3 years with EBRT to 65–70 Gy leads to improved overall survival.
In the aforementioned retrospective analysis of patients treated with brachytherapy and supplemental EBRT, there was no difference seen between less than 6 months vs more than 6 months of ADT. This may be a reflection of response in patients with a more favorable risk profile; that is, longer-term ADT does not confer additional benefit in this group. Based on this finding, a shorter course may be adequate with brachytherapy.
The optimal timing of androgen suppression is not entirely clear, as the key EBRT trials used adjuvant; neoadjuvant and concurrent; concurrent and adjuvant; as well as neoadjuvant, concurrent, and adjuvant regimens. The interaction of androgen suppression with radiation is complex, as evidenced by the results of RTOG 94-13, which showed survival improvement with neoadjuvant and concurrent ADT with pelvic radiation, but a survival detriment with short-term adjuvant ADT. Given the observed in vitro synergistic effects, most would advocate for concurrent ADT with EBRT, if it is to be given.
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