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Androgen Deprivation Therapy: Appropriate Patients, Timing to Initiate ADT, and Complications
Introduction
Prostate cancer is the second most frequently diagnosed cancer of men and the sixth leading cause of death in men with close to 258,000 deaths reported worldwide. In the United States alone, prostate cancer is the second leading cause of cancer mortality. Metastatic castration-resistant prostate cancer (CRPC) is almost always associated with death in patients with prostate cancer. The seminal observation that resulted in the development of ADT occurred in the 1940s when Dr Huggins and Hodges discovered the role of androgen in prostate cancer at the University of Chicago. They showed that prostate cancer cell growth and spread were dependent on hormonal signaling. Huggins and Hodges were awarded the Nobel Prize in 1966 for their discovery of the androgen-dependent nature of prostate cancer. This vulnerability of prostate cancer was exploited for over half a century until new therapeutic agents were discovered and utilized at the turn of the century. Nevertheless, androgen deprivation therapy (ADT) still remains the foundation of advanced prostate cancer care.
Androgen deprivation therapy
The use of ADT leveled after peaking in the 1990s. Indeed, Shahinian et al. reported a substantial decline in the usage of ADT as a primary treatment modality for localized, low- to moderate-grade prostate cancer from 38.7% in 2003 to 30.6% and 25.7% in 2004 and 2005, respectively. Nevertheless, Cetin et al. estimated that on December 31, 2008, 188, 916 men aged ≥45 with nonmetastatic prostate cancer in the United States were receiving continuous ADT therapy for ≥6 months. In addition, Kuykendal et al. analyzed the Surveillance Epidemiology and End Results-Medicare database and reported that 12.4% of men with nonmetastatic prostate cancer aged 66–80 years received ADT discordant with published NCCN guidelines.
Although primary ADT has no survival benefit in men with clinically localized prostate cancer, ADT is beneficial in some clinical settings. Specifically, the combination of ADT with radiation provides a superior survival in men with intermediate- or high-risk prostate cancer ( Table 52.1 ). Similarly, adjuvant ADT improves survival in patients with positive lymph node after radical prostatectomy ( Table 52.2 ). Notwithstanding, ADT is most frequently used in a palliative role in metastatic prostate cancer.
Table 52.1
ADT with Radiation
| Trials | Groups | Sample size | 10-year overall survival * | 10-year cancer-specific mortality * |
|---|---|---|---|---|
| Pilepich et al. (RTOG 85-31) | RT + life time adjuvant ADT versus RT + ADT as relapse | 477 Versus 468 | 49% Versus 39% | 16% Versus 22% |
| Bolla et al. (EORTC 22863) | RT versus RT + immediate ADT for 3 years | 208 Versus 207 | 39.8% Versus 58.1% | 30.4% Versus 10.3% |
| Widmark et al. | 3 Months flutamide versus 3 months flutamide + RT | 439 Versus 436 | 60.6% Versus 70.4% | 23.9% Versus 11.9% |
| Warde et al. | Lifelong ADT versus Lifelong ADT + RT | 662 Versus 603 | 66% Versus 74% ** | 19% Versus 9% ** |
| Horwitz et al. (RTOG 92-02) | 4 Months ADT + RT versus 24 months ADT + RT | 763 Versus 758 | 51.6% Versus 53.9% † | 16.1% Versus 11.3% |
| Bolla et al. (EORTC 22961) | 6 Months ADT + RT versus 3 years ADT + RT | 483 Versus 487 | 81% Versus 84.8% ‡ | 4.7% Versus 3.2% ‡ |
| Roach et al. (RTOG 86-10) | 2 Months neoadjuvant and 2 months concurrent ADT + RT versus RT | 224 Versus 232 | 43% Versus 34% § | 23% Versus 36% |
| Jones et al. (RTOG 94-08) | 2 Months neoadjuvant and 2 months concurrent ADT + RT versus RT | 987 Versus 992 | 62% Versus 57% | 4% Versus 8% |
| Denham et al. (TROG 96.01) | 3 Months versus 6 months neoadjuvant ADT + RT versus only RT | 265 Versus 267 versus 270 | 63.3% Versus 70.8% versus 57.5% ¶ | 18.9% Versus 11.4% versus 22% ¶ |
* All differences are significant, unless otherwise stated.
** Seven-year overall survival and cancer specific mortality.
† Difference not significant; 24 months ADT had survival benefit in a subgroup of patients with Gleason score of 8 to 10.
‡ Five-year overall survival and cancer specific mortality.
¶ No significant difference between 3 months neoadjuvant ADT and only RT groups.
Table 52.2
Radical Prostatectomy and ADT
| Study | Clinical stage | Design | Follow-up (years) | Overall survival | Progression-free survival |
|---|---|---|---|---|---|
| Shelley et al. | Localized ± LN metastasis | Meta-analysis of trials with neoadjuvant ADT | – | No change | No change |
| Yee et al. | Localized | 3 Months of neoadjuvant ADT + RP versus RP | 8 | No change | No change |
| Wirth et al. | Localized | RP versus RP + adjuvant flutamide | 6.1 | No change | Better in flutamide group |
| Siddiqui et al. | Localized | Effect of timing of adjuvant ADT after RP | 10 | No change | Better if it starts before recurrence |
| Messing et al. | LN metastasis | RP + Immediate ADT versus ADT after recurrence | 11.9 | Better with immediate ADT | Better with immediate ADT |
| Dorff et al. | LN metastasis | RP + 2 years of adjuvant ADT alone versus ADT + mitoxantrone | 4.4 | Better than expected in ADT only group * | Better than expected in ADT only group * |
* This trial was closed early after three cases of acute myelogenous leukemia were reported in the mitoxantrone treatment arm.
Combination therapy
Neoadjuvant ADT With Radical Prostatectomy
The concept of neoadjuvant hormone therapy before prostate surgery was evaluated in multiple clinical trials ( Table 52.2 ). Shelley et al. published a systematic review and meta-analysis of randomized trials to evaluate the efficacy of neoadjuvant hormone therapy before prostatectomy for localized and locally advanced prostate cancer. This study showed that 3 months of neoadjuvant hormone therapy prior to prostatectomy is associated with significant reduction in positive margin rates (RR 0.49, 95% CI (confidence interval) 0.42–0.56, p < 0.00001), increase in organ-confined disease (RR 1.63, 95% CI 1.37–1.95, p < 0.0001), and reduction in lymph node invasion (RR 0.49, 95% CI 0.42–0.56, p < 0.02). However, it did not improve disease-specific, disease-free, and overall survival. Recently, Yee et al. confirmed these results in long-term follow-up of a randomized trial of radical prostatectomy with or without a 3-month course of neoadjuvant hormone (goserelin acetate and flutamide) for clinically localized prostate cancer. At median follow-up of 8 years, there was no significant difference in biochemical recurrence rates between the two groups. It also showed no significant relationship between neoadjuvant hormone therapy and biochemical recurrence. The lack of a clear survival advantage, cost, and side effects of neoadjuvant ADT before radical prostatectomy strongly suggest that neoadjuvant ADT is not indicated in men undergoing surgery.
ADT With Radiation
ADT is now recommended for radiation therapy in patients with intermediate-risk disease with adverse features and high-risk prostate cancer ( Table 52.1 ). Pilepich et al. (RTOG 85-31) randomized patients with clinical stage T3 or lymph node stage N1 to either radiation and lifetime adjuvant goserelin or radiation alone and delayed goserelin at relapse. At 10 years, the overall survival rate was superior in the lifetime adjuvant group compared to only radiation group (49% vs. 39%, p = 0.002). Bolla et al. (EORTC 22863) also evaluated the efficacy of long-term ADT (3 years) with radiation therapy in patients with clinical stage T1–T2 World Health Organization grade 3 or T3–T4 N0–N1 prostate cancer. Again, 10-year clinical disease-free survival and overall survival was significantly higher in the combined treatment group versus the radiotherapy-alone group.
Two additional studies investigated the role of radiation therapy in combination with ADT. Widmark et al. randomized men with locally advanced prostate cancer (T3, N0, M0) to ADT alone or to the same endocrine treatment combined with radiation therapy. The cumulative incidence of prostate-cancer-specific mortality and overall mortality at 10 years was significantly lower in the combination group. In the second trial, Warde et al. compared the overall survival in men with locally advanced prostate cancer managed with ADT alone or ADT with radiation, and found that addition of radiation to ADT improved overall survival at 7 years with minimal side effects.
Largely based on these studies, long-term (2–3 years) ADT in combination with radiation therapy is indicated for patients with high to very high risk of progression while short-term ADT (4–6 months) in combination with radiation is a viable option in men with intermediate-risk prostate cancer. Horwitz et al. (RTOG 92-02) compared the efficacy of 4 months of goserelin and flutamide before and during radiation therapy versus 24 months of ADT in 1554 patients with T2c–T4, N0, M0 prostate cancer. At 10 years, long-term ADT improved disease-free survival, disease-specific survival, local progression, distant metastasis, and biochemical failure. It had no effect on overall survival. However, long-term ADT had survival benefit in a subgroup of patients with Gleason score of 8 to 10. Furthermore, Bolla et al. (EORTC 22961) demonstrated that short-term (6 months) androgen suppression with radiation therapy provides inferior survival in locally advanced disease compared with radiotherapy plus 3 years of androgen suppression at intermediate-term follow up.
More recently, short-term (4–6 months) neoadjuvant hormone therapy has been shown to have survival benefit over radiation therapy alone. Roach et al. (RTOG 86-10) reported that overall survival is higher in patients with locally advanced prostate cancer who received ADT 2 months before and concurrent with radiation (total 4 months) versus radiation alone. However, this difference did not reach statistical significance. In contrast, Jones et al. (RTOG 94-08) evaluated the efficacy of the same neoadjuvant ADT in a cohort of patients with low- and intermediate-risk prostate cancer and showed at a median follow-up of 9.1 years, short-term (4 months) ADT has a significant survival benefit compared with radiation therapy alone. Denham et al. (TROG 96.01) compared the 3-month and 6-month neoadjuvant ADT combined with radiation for locally advanced prostate cancer. In this study 3 months ADT had no effect on prostate-cancer-specific mortality or all-cause mortality compared with radiotherapy alone. However, 6-month ADT had a survival benefit after a median follow-up of 10.6 years compared with radiotherapy alone. Finally, the outcomes of short-term (4 months) and long-term (8 months) neoadjuvant ADT before radiotherapy was assessed in patients with localized prostate cancer and it was found that at median of 102 months, survival, biochemical failure-free survival, and prostate-cancer-specific survival did not differ significantly between the two groups.
Combined Androgen Blockade
The concept of adding an antiandrogen to surgical or medical castration is based on the observation that androgens secreted from the adrenal gland after castration can cause prostate cancer progression. In the 1990s, the efficacy of combined androgen blockage (CAB) using nilutamide and flutamide was investigated in multiple clinical trials. The collaborative meta-analysis of 27 randomized trials on the combination of an antiandrogen (nilutamide, flutamide, or cyproterone acetate) with either surgical castration or a luteinizing hormone-releasing hormone (LHRH) agonist showed no significant 5-year survival benefit in the CAB group versus the androgen suppression group. In this study, most patients (88%) had metastatic disease while the remainder had locally advanced disease. In a separate systematic review and meta-analysis, Samson et al. compared monotherapy and CAB in men with advanced prostate cancer. Although, they found no statistically significant difference in survival at 2 years, there was a statistically significant difference in survival at 5 years in the CAB group versus monotherapy. Klotz et al. reanalyzed the clinical trials of CAB and found that CAB with 50 mg bicalutamide reduced the risk of death by 20% compared with castration alone. In a phase 3 trial, Akaza et al. compared CAB with LHRH agonist plus bicalutamide 80 mg versus LHRH agonist monotherapy in patients with advanced prostate cancer. At a median follow-up of 5.2 years, a significant overall survival advantage was observed in the CAB group over LHRH agonist monotherapy. Taken together, CAB provides a modest survival benefit compared with monotherapy in the management of advanced prostate cancer.
Timing
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