Most men treated with radical prostatectomy or radiation therapy for localized prostate cancer will be cured of prostate cancer; however, some men will experience treatment failure. Androgen deprivation therapy is well established in the treatment of metastatic prostate cancer. Adjuvant androgen deprivation therapy, following prostatectomy and/or radiotherapy, has been studied in the high-risk prostate cancer setting to try to reduce the risk of recurrence and improve patient outcomes. In this review, we discuss the current data for neoadjuvant and adjuvant therapy with androgen suppression, chemotherapy, and approaches with the newer hormonal agents.
Key points
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Adjuvant androgen deprivation therapy is well-established in conjunction with RT for intermediate- and high-risk disease.
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The role of hormone therapy is less clear in patients who undergo a prostatectomy.
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Further exploration and patient selection is needed to better define the roles of ADT alone, androgen-AR axis modifications, and chemotherapy in the adjuvant setting.
Introduction
Among the 241,000 men who are diagnosed with prostate cancer each year, 82% will have localized disease and 11% will have regional or locally advanced disease. Most men treated with radical prostatectomy or radiation therapy (RT) will be cured of prostate cancer. However, some men will experience treatment failure. The factors that increase the risk of cancer recurrence after primary therapies include extraprostatic (T3 or T4) disease, pretreatment prostate-specific antigen (PSA) greater than 20 ng/mL, Gleason score of 8 or more, perineural invasion on biopsy, and seminal vesicle involvement or positive margins in the prostatectomy specimen. Androgen deprivation therapy (ADT) is well established in the treatment of metastatic prostate cancer. Adjuvant hormone therapy, following prostatectomy and/or radiotherapy, has been studied in the high-risk prostate cancer setting to try to reduce the risk of recurrence and improve patient outcomes. Its role in localized cancer is well established in conjunction with RT for intermediate- and high-risk disease but is far less clear in patients who undergo a prostatectomy.
Introduction
Among the 241,000 men who are diagnosed with prostate cancer each year, 82% will have localized disease and 11% will have regional or locally advanced disease. Most men treated with radical prostatectomy or radiation therapy (RT) will be cured of prostate cancer. However, some men will experience treatment failure. The factors that increase the risk of cancer recurrence after primary therapies include extraprostatic (T3 or T4) disease, pretreatment prostate-specific antigen (PSA) greater than 20 ng/mL, Gleason score of 8 or more, perineural invasion on biopsy, and seminal vesicle involvement or positive margins in the prostatectomy specimen. Androgen deprivation therapy (ADT) is well established in the treatment of metastatic prostate cancer. Adjuvant hormone therapy, following prostatectomy and/or radiotherapy, has been studied in the high-risk prostate cancer setting to try to reduce the risk of recurrence and improve patient outcomes. Its role in localized cancer is well established in conjunction with RT for intermediate- and high-risk disease but is far less clear in patients who undergo a prostatectomy.
Adjuvant hormone therapy following prostatectomy
There have been limited studies evaluating the role of adjuvant hormone therapy following prostatectomy ( Table 1 ). The Eastern Cooperative Oncology Group study (ECOG 3886) evaluated immediate versus deferred ADT in men with node-positive prostate cancer. Between 1988 and 1993, 98 men who underwent a radical prostatectomy and pelvic lymphadenectomy and found to have microscopic lymph node metastases were randomized to receive immediate lifelong ADT or to be observed and receive ADT on symptomatic recurrence or detection of distant metastatic disease. At a median follow-up of 11.9 years, the men assigned to the immediate ADT arm had a significant improvement in overall survival (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.01–3.35, P = .04), prostate cancer–specific survival (HR 4.09, CI 1.76–9.49, P = .0004), and progression-free survival (PFS) (HR 3.42, CI 1.96–5.98, P <.0001). In this study, patients in the observation arm were initiated on ADT only after the development of symptomatic recurrence or detectable metastatic disease and not at the time of biochemical recurrence, which can occur at a median of 8 years before the onset of radiologic evidence of metastatic disease.
| Study | ECOG 3886 (Messing) | SEER Retrospective (Wong) | Adjuvant Flutamide (Wirth) | Adjuvant Bicalutamide (Iverson) | ||||
|---|---|---|---|---|---|---|---|---|
| Design | Immediate vs deferred ADT | Adjuvant ADT vs no ADT | Flutamide vs observation | Bicalutamide vs observation | ||||
| Immediate | Deferred | Adjuvant | No adjuvant | Flutamide | Observation | Bicalutamide | Placebo | |
| Median Biochemical PFS (y) | 13.9 | 2.4 ( P <.0001) | Not reported | Not reported | 10.8 | 9.9 ( P = .0041) | 6.6 | 3.7 ( P = .001) |
| HR 3.42 (95% CI 1.96–5.98) | — | HR 0.51 (95% CI 0.32–0.81) | HR 0.85 (95% CI 0.79–0.91) | |||||
| Median Disease-Specific Survival (y) | Not reached | 12.3 ( P = .0004) | Not reached | Not reached (NS) | Not reported | Not reported | Not reported | Not reported |
| HR 4.09 (95% CI 1.76–9.49) | HR 0.97 (95% CI 0.56–1.68) | — | — | |||||
| Median Overall Survival (y) | 13.9 | 11.3 ( P = .04) | Not reached | Not reached (NS) | 11 a | Not reached (NS) | Not reached | Not reached (NS) |
| HR 1.84 (95% CI 1.01–3.35) | HR 0.95 (95% CI 0.71–1.27) | HR 1.04 (95% CI 0.53–2.02) | HR 1.01 (95% CI 0.94–1.09) | |||||
a Data not reported in primary article and estimated from available survival curves.
A separate retrospective observational study using Surveillance, Epidemiology, and End Results (SEER)–Medicare data was done to evaluate the impact of adjuvant ADT for patients who have node-positive prostate cancer in the contemporary era of postoperative PSA surveillance to detect biochemical recurrence. Wong and colleagues used the SEER-Medicare database to construct a cohort of men with lymph node–positive disease who had undergone radical prostatectomy between 1991 and 1999 and classified them as receiving adjuvant ADT (within 120 days of radical prostatectomy) or not receiving adjuvant ADT (subsequent ADT initiated >120 days from surgery or no ADT). Among the 731 men identified, 209 had received ADT within 120 days of radical prostatectomy. After adjusting for potential confounders of receiving adjuvant ADT (ie, tumor characteristics, extent of nodal disease, demographics, receipt of RT), there was no statistically significant difference in the overall survival between the adjuvant ADT and non-ADT group (HR 0.97, 95% CI 0.71–1.27). Additionally, there was no statistically significant survival difference when various definitions of adjuvant ADT (90, 150, 180, and 365 days) were tested. One important limitation of this study is that the indication for ADT (adjuvant vs salvage) was not available through the database.
In the SWOG (Southwest Oncology Group) S9921 trial, 983 men with high-risk prostate cancer (extraprostatic extension, positive nodes, positive margin Gleason 7 or Gleason grade >7) received adjuvant therapy with ADT (goserelin and bicalutamide for 2 years) alone or in combination with 6 cycles of mitoxantrone chemotherapy after a prostatectomy. For the 481 men who received ADT only, the estimated 5-year biochemical failure-free survival was 92.5% (95% CI 90–95) and the 5-year overall survival was 95.9% (95% CI 93.9–97.9). This trial was closed to accrual in January 2007 after 3 cases of acute myelogenous leukemia were reported in the mitoxantrone treatment arm. The final analysis of the primary end point of overall survival comparing the 2 arms for this trial has not been reported; however, the results seen in the ADT-only arm make a compelling argument to counsel patients with high-risk prostate cancer about adjuvant ADT after a prostatectomy. This study represents the largest prospective cohort of patients with high-risk prostate cancer receiving adjuvant ADT and showed favorable results.
The use of antiandrogen therapy alone in the adjuvant setting has also been investigated. Wirth and colleagues studied the role of adjuvant flutamide therapy in 309 patients with locally advanced, lymph node–negative prostate cancer who were randomized to receive either flutamide or observation after a prostatectomy. At a median follow-up of 6.1 years, flutamide treatment was associated with considerable toxicity; although it showed improved recurrence-free survival ( P = .0041), it did not improve the overall survival ( P = .92). The Early Prostate Cancer Program was an international program consisting of 3 randomized, double-blind, placebo-controlled clinical trials. Men with localized or locally advanced prostate cancer were randomized to receive either oral bicalutamide 150 mg once daily or oral placebo in addition to standard care with radical prostatectomy, radiotherapy, or watchful waiting. In all, 8113 patients with localized (T1–2, N0/Nx) or locally advanced (T3–4, any N; or any T, N+) prostate cancer (all M0) were enrolled in 3 complementary double-blind, placebo-controlled trials. At a median follow-up of 9.7 years, bicalutamide significantly improved PFS (HR 0.85, 95% CI 0.79–0.91, P = .001) compared with placebo; however, there was no difference in overall survival (HR 1.01, P = .77). Moreover, the improvement in PFS was observed in patients with locally advanced prostate cancer but not in patients with localized disease. In a subset analysis, the overall survival benefit was demonstrated in patients with locally advanced disease undergoing radiotherapy ( P = .031).
Based on data from the ECOG 3886 and the SWOG S9921 studies, it may be reasonable to consider adjuvant ADT in some patients with lymph node–positive or high-risk prostate cancer after a prostatectomy, especially in patients who may not be candidates for adjuvant radiation (discussed later). Given the lack of an overall survival benefit from the flutamide and bicalutamide studies, the use of antiandrogen therapy alone in the adjuvant setting is generally not recommended.
Adjuvant RT following prostatectomy
The use of adjuvant RT alone for high-risk disease following prostatectomy has been studied by the European Organization for Research and Treatment of Cancer (EORTC) 22911 and SWOG 8794 trials and the Arbeitsgemeinschaft Radiologische Onkologie und Urologische Onkologie of the German Cancer Society (ARO 96-02/AUO AP 09/95). Table 2 summarizes these trials.
| Study | EORTC 22911 (Bolla) | SWOG S8794 (Thompson) | ARO 96-02/AUO AP 09/95 (Wiegel) | |||
|---|---|---|---|---|---|---|
| Design | Immediate postoperative irradiation vs wait-and-see approach | Immediate postoperative irradiation vs observation | Immediate postoperative irradiation vs wait-and-see approach | |||
| Postoperative irradiation (60 Gy) | Wait-and-see | Postoperative irradiation (60–64 Gy) | Observation | Postoperative irradiation (60 Gy) | Wait-and-see | |
| Median Biochemical PFS (y) | 13.2 | 6.12 | 10.3 | 3.1 | Not reported | Not reported |
| HR 0.49 (95% CI 0.41–1.59) | HR 0.43 (95% CI 0.31–0.58, P <.001) | Biochemical NED at 10 y 56% vs 35% (HR 0.51, P = .00002) | ||||
| Median DSS (y) | Not reported | Not reported | 13.8 | 9.9 | Not reported | Not reported |
| DSS at 10 y 96.1% vs 94.6%, HR 0.78 (95% CI 0.46–1.33, P = .3407) | HR 0.62 (95% CI 0.46–0.82, P = .001) | — | ||||
| Median OS (y) | Not reached | 15.6 a | 15.2 | 13.3 | Not reached | Not reached |
| OS at 10 y 76.9% vs 80.7% ( P = .2024) | (HR, 0.72, 95% CI 0.55–0.96, P = .023) | P = .59 | ||||
a Data not reported in primary article and estimated from available survival curves.
EORTC 22911 was a phase III trial comparing immediate postoperative RT (60 Gy conventional) versus the wait-and-see approach in which patients underwent RT at the time of biochemical recurrence (PSA >0.2, confirmed >2 weeks apart). There were 1005 patients enrolled in this study. At 10.6 years of follow-up, 39.4% in the immediate RT group experienced biochemical progression, clinical progression, or death compared with 61.8% in the wait-and-see group. There was no difference in overall survival between the treatment groups (HR 1.18, 95% CI 0.91–1.53, P = .2024), with a 10-year survival of 76.9% (95% CI 72.4–80.8) in the postoperative irradiation group compared with 80.7% (76.4–84.3) in the wait-and-see group. There was an increase in late effects seen in patients treated with immediate postoperative RT.
SWOG S8794 evaluated 425 men with pathologically advanced prostate cancer who had undergone radical prostatectomy, randomized to receive 60 to 64 Gy of external beam radiotherapy delivered to the prostatic fossa (n = 214) or usual care plus observation (n = 211). The primary outcome was metastasis-free survival; the secondary outcomes included PSA relapse, recurrence-free survival, overall survival, freedom from hormonal therapy, and postoperative complications. At a median follow-up of 10.6 years (interquartile range 9.2–12.7 years), 76 (35.5%) of 214 men in the adjuvant radiotherapy group were diagnosed with metastatic disease or died (median metastasis-free estimate 14.7 years) compared with 91 (43.1%) of 211 (median metastasis-free estimate 13.2 years) of those in the observation group (HR 0.75, 95% CI 0.55–1.02, P = .06). Radiotherapy also significantly reduced the rates of PSA relapse (median PSA relapse-free survival 10.3 years for radiotherapy vs 3.1 years for observation, HR 0.43, 95% CI 0.31–0.58, P <.001) and disease recurrence (median recurrence-free survival 13.8 years for radiotherapy vs 9.9 years for observation, HR 0.62, 95% CI 0.46–0.82, P = .001). With a longer follow-up of 12.7 years for the radiotherapy arm and 12.5 years for the observation arm, a survival advantage was seen. The median overall survival was 13.3 years in the observation arm and 15.2 years in the radiotherapy arm (HR 0.72, 95% CI 0.55–0.96, P = .023).
The ARO German study (96-02/AUO AP 09/95) randomly assigned 192 men with PT3N0 prostate cancers who achieved undetectable PSA to receive immediate postoperative RT (60 Gy) or the wait-and-see approach. At 5 years, the biochemical PFS was significantly improved in the RT group compared with observation (72% vs 54%, P = .0015). At 10 years, RT improved biochemical control by 49% (freedom from biochemical failure [bNED] 56% vs 35%, HR 0.51, P = .00002). There was no difference in metastases-free survival ( P = .56) or overall survival ( P = .59), although the study was not powered to detect differences in overall survival.
The timing of radiotherapy after radical prostatectomy is still controversial. Studies are ongoing to determine the best setting (adjuvant vs salvage) for radiotherapy, including the Trans-Tasman Radiation Oncology Group Radiotherapy, Adjuvant versus Early Salvage (RAVES) study ( ClinicalTrials.gov , identifier NCT00860652 ) and the Medical Research Council Radiation Therapy and Androgen Deprivation Therapy in Treating Patients Who Have Undergone Surgery for Prostate Cancer (RADICALS) study ( ClinicalTrials.gov , identifier NCT00541047 ).
Adjuvant androgen deprivation therapy in combination with RT
The benefit of combining ADT to external beam RT (EBRT), compared with EBRT alone in patients with clinically localized prostate cancer with prostate gland intact, has been demonstrated repeatedly in multiple trials. However, the optimum duration of ADT in this setting is still controversial and varies based on the risk category. Table 3 summarizes the clinical trials evaluating adjuvant ADT in combination with RT.
| Study | RTOG 85-31 (Pilepich) | RTOG 86-10 (Pilepich, Roach) | RTOG 92-02 (Horwitz) | EORTC 22863 (Bolla) | ||||
|---|---|---|---|---|---|---|---|---|
| Design | EBRT + adjuvant ADT vs EBRT + salvage ADT (65–70 Gy if no prior RP, 60–65 Gy if prior RP) | EBRT alone vs EBRT + ST ADT (65–72 Gy) | EBRT plus ST (4 mo) vs LT ADT (2 y) (65–70 Gy) | EBRT alone vs EBRT + LT ADT (3 y) (70 Gy) | ||||
| Adjuvant | Salvage | EBRT alone | EBRT + ST ADT | ST ADT | LT ADT | EBRT alone | EBRT + LT ADT | |
| Median Biochemical PFS (y) | Not reported | Not reported | Not reported | Not reported | 2.5 a | 7.5 a | Not reported | Not reported |
| PFS at 10 y, 37% vs 23% ( P <.0001) | PFS at 10 y, 11.2% vs 3.4% ( P <.0001) HR 1.97 (95% CI 1.61–2.42) | PFS at 10 y, 13% vs 23% ( P <.0001) | Median clinical PFS 4 a y vs 9 a y, clinical PFS at 10 y, 23% vs 48% ( P <.0001), HR 0.42 (95% CI 0.33–0.55) | |||||
| Median DSS (y) | Not reached | Not reached | Not reached | Not reached | Not reached | Not reached | Not reached | Not reached |
| DSS at 10 y, 84% vs 78% ( P = .0052) | DSS at 10 y, 77% vs 64% ( P = .01), HR 1.52 (95% CI 1.09–2.13) | DSS at 10 y, 84% vs 89% ( P = .0042), HR 0.657 (95% CI 0.504–0.857) | DSS at 10 y, 70% vs 90% ( P <.0001), HR 0.38 (95% CI 0.24–0.60) | |||||
| Median OS (y) | 10 a | 8 a | 7.3 | 8.7 (NS) | Not reached | Not reached | 7 a | 11 a |
| OS at 10 y, 49% vs 39% ( P = .002) | OS at 10 y, 43% vs 34% ( P = .12), HR 1.05 (95% CI 0.84–1.31) | OS at 10 y, 52% vs 54% ( P = .36), HR 0.922 (95% CI 0.904–1.057) | OS at 10 y, 40% vs 58% ( P = .0004), HR 0.60 (95% CI 0.45–0.80) | |||||
Related posts:
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Management of Hormone-Sensitive Metastatic Prostate Cancer
Contemporary Issues in Radiotherapy for Clinically Localized Prostate Cancer
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