2. UroToday Home
  3. Archives
  4. CME

CME - The Role, Timing, and Clinical Utility of Hormone Therapy in Prostate Cancer

Learning Objectives

At the conclusion of this activity, participants should be able to:

  • identify patients who could benefit from hormone therapy, 
  • list current hormone therapies available for the treatment of biochemical recurrence as well as advanced and metastatic prostate cancer,
  • discuss the importance of achieving balance among disease control, toxicity minimization, and treatment tolerance,
  • explain the role of monotherapy and combination hormone therapy for advanced prostate cancer, and
  • identify factors influencing the controversies of timing, institution of alternative therapies, and continuous versus intermittent administration of treatment for patients with advanced prostate cancer, castrate-resistant prostate cancer, and biochemical recurrence 

Target Audience

This activity is designed for urologists and other health care professionals interested in or involved with the management of patients with prostate cancer. 

Faculty

Pamela I. Ellsworth, MD (Program Chair)

Associate Professor of Surgery, Division of Urology, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA 

Fred Saad, MD, FRCS

Professor and Chairman of Urology, Director of Urologic Oncology, University of Montreal Endowed Chair in Prostate Cancer, University of Montreal Faculty of Medicine, Montreal, Canada 

Presented by the Warren Alpert Medical School of Brown University, Office of Continuing Medical Education. This activity is supported by an educational grant from Abbott Laboratories. 

Faculty Disclosures

In accordance with the disclosure policy of the Warren Alpert Medical School of Brown University as well as standards set forth by the Accreditation Council for Continuing Medical Education, all speakers and individuals in a position to control the content of a CME activity are required to disclose relevant financial relationships with commercial interests (within the past 12 months). Disclosures of this activity’s speakers and planning committee have been reviewed and all identified conflicts of interest, if applicable, have been resolved. 

Pamela I. Ellsworth, MD, has indicated that she is a consultant/advisory board member for Allergan, Inc., Astellas Pharma US, Inc., and Pfizer Inc. She is a speaker for Allergan, Inc. and Pfizer Inc. 

Fred Saad, MD, FRCS, has indicated that he has received grant/research support from and has served as a consultant/advisory board member for Abbott, Amgen, Astellas Pharma US, Inc., Janssen, Millennium Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, and Sanofi Aventis. 

Activity Staff Disclosures

The planners, reviewers, editors, staff, or other members at Health and Wellness Education Partners and the Alpert Medical School CME Office who control content have no relevant financial relationships to disclose.

Accreditation Statement

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Warren Alpert Medical School of Brown University and Health and Wellness Education Partners. The Warren Alpert Medical School is accredited by the ACCME to provide continuing medical education for physicians. 

Credit Designation Statement

The Warren Alpert Medical School designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Method of Participation/CME Credit

  • There are no prerequisites or fees for participating in and receiving credit for this activity.
  • Review the learning objectives, faculty information, and CME information.
  • Complete the CME activity.
  • Complete the post-test and activity evaluation at the conclusion of the activity. A minimum score of 80% is required to receive a CME credit certificate. Click here. 
  • A CME credit certificate will be emailed to you within 4 weeks. 

Program Release: May 29, 2012

Program Expiration: May 31, 2013

Estimated time to complete: 60 minutes

There are no prerequisites for participation. 

The Office of Continuing Medical Education (CME) is committed to protect the privacy of its members and customers. The CME Office maintains its Internet site as an information resource and service for physicians, other health professionals, and the public. The CME Office will keep your personal information confidential when you participate in a CME Internet-based program. CME collects only the information necessary to provide you with the services that you request. 

This enduring material is produced for educational purposes only. Content is provided by faculty who have been selected because of recognized expertise in their field. The opinions and recommendations expressed by the faculty whose input is included in this activity are their own. The use of the Warren Alpert Medical School of Brown University name implies oversight and review by the CME Office of educational content, format, design, and approach. Participants have the professional responsibility to review the complete prescribing information of specific drugs or combination of drugs including indications, contraindications, warnings, and adverse effects before administering pharmacologic therapy to patients. The Warren Alpert School of Medicine of Brown University assumes no liability for the information herein.

Contact Information

If you have questions about this CME activity, please contact the Warren Alpert Medical School Office of Continuing Medical Education at 1-401-863-3337 or .

INTRODUCTION

Prostate cancer is the second-leading cause of cancer death in men in the United States, accounting for 28,170 deaths annually [1]. It accounts for approximately 29% of new cancer cases and an estimated 9% of cancer-related deaths in men [1]; most prostate cancer-related deaths are caused by advanced disease. However, with earlier diagnosis and the development of new treatment options for early and advanced disease, there has been a gradual but steady decline in prostate cancer mortality [2,3].

With earlier detection and treatment for disease at all stages, including advanced disease, the age-adjusted incidence of stage IV prostate cancer has been declining [4]. However, with more men living longer with prostate cancer, it is expected that more of them will eventually present with rising prostate-specific antigen (PSA) levels that require further treatment. 

Defining Advanced Disease

Biochemical recurrence, a rise in PSA after treatment with surgery or radiation, occurs in approximately 40% of men receiving localized treatment [5,6], and has become the most common form of advanced prostate cancer [7,8,9]. Other categories of patients also can be defined as having advanced forms of the disease: patients with significant risk for progressive disease and/or death from prostate cancer should be included in the definition of advanced prostate cancer [10]. Likewise, those men with cancer outside the prostate capsule (with disease stages as low as T3/N0/M0) are considered to have advanced disease [11,12]. With high-risk localized disease and biochemical recurrence as common presentations of advanced prostate cancer, most of these patients are entering into treatment long before they develop metastases [10]. In the absence of guidelines for treating patients with advanced disease in whom local therapy has failed, the decision algorithm for initiation of treatment for biochemical recurrence remains controversial. Patient- and drug-related factors to be considered include the previous local therapy, the patient’s life expectancy and quality of life (QOL), the risk for increased morbidity, and the likelihood of cure/palliative therapy.

Treatment of Advanced Disease

Androgen deprivation therapy (ADT), the use of gonadotropin-releasing hormone (GnRH) agonist/antagonists with or without antiandrogens, continues to be first-line therapy in men with advanced and/or metastatic prostate cancer. Once it was approved, GnRH agonist therapy replaced bilateral orchiectomy in initial ADT, because of the potential for reversal and the lack of the emotional stigma associated with surgical castration [13]. Currently, there is a single GnRH antagonist and several GnRH agonists available that vary in their frequency of dosing and method of administration (Table 1). 

A meta-analysis of 24 randomized controlled trials involving more than 6000 patients found that survival with GnRH agonists is equivalent to that after orchiectomy [14]. Although approved for the treatment of advanced prostate cancer, GnRH agonists have been used in other prostate cancer settings, including primary therapy for older patients with locally advanced prostate cancer, treatment of patients with biochemical recurrence after radical prostatectomy or external beam radiation therapy (EBRT), and neoadjuvant or adjuvant treatment for high-risk patients undergoing prostatectomy or EBRT [13]. Notably, ADT has increased steadily throughout the 1990s among men of all ages with prostate cancer who had all stages and tumor grades [15].

The optimal timing for starting ADT in various prostate cancer settings remains controversial, because of the potential for adverse effects (AEs) and emergence of castrate-resistant prostate cancer (CRPC) as a result of widespread and long-term use of treatment. Antiandrogens are approved by the US Food and Drug Administration (FDA) for the treatment of advanced prostate cancer in combination with a GnRH agonist/antagonist (combined androgen-deprivation therapy {CADT}), but they are not approved for use as monotherapy. This article provides a review of the data on the use and timing of ADT (monotherapy with a GnRH agonist/antagonist) and CADT in various prostate cancer settings, as well as the role of intermittent ADT in decreasing AEs, maintaining efficacy, and delaying emergence of CRPC in patients with advanced disease. Side effects of ADT/CADT and ways to prevent or manage them are also discussed. 

Optimal Timing of ADT

Timing of ADT in Advanced Disease

The optimal time to begin ADT in prostate cancer varies with the disease state. The optimal timing in an asymptomatic man with PSA failure alone is not known, but in practice, most men in North America opt for earlier rather than late treatment. Recent literature supports that early intervention with ADT is more beneficial than treatment initiated later in the disease course [16,17]. 

Patients with advanced disease also appear to benefit from early hormonal therapy. The Medical Research Council in England conducted a randomized controlled trial of 938 patients with locally advanced or asymptomatic metastatic prostate cancer [18]. The trial compared patients who received immediate ADT (orchiectomy or GnRH agonist/antagonist) within 6 weeks of entry versus those who deferred treatment until an indication for ADT occurred. Of the 938 patients, 600 (53%) had nonmetastatic disease at the time of enrollment and had follow-up information available. 

Results showed that immediate ADT significantly improved cause-specific survival of patients with confirmed nonmetastatic disease compared with deferred treatment. The median actuarial cause-specific survival duration was 7.5 years for immediate treatment and 5.8 years for deferred treatment (P = 0.003). Additionally, the incidence of tumor-related morbidity associated with immediate treatment was lower than with deferred treatment [18]. 

Timing of ADT in Other Settings, With or Without EBRT

Biochemical recurrence, a rise in PSA in prostate cancer patients after treatment with surgery or radiation, is not uncommon. In fact, biochemical recurrences in the setting of prior definitive therapy are estimated to affect approximately 30% of men treated for localized prostate cancer [7,8,9]. The natural history of disease relapse after radical prostatectomy involves development of metastases and eventual death, usually over a period of several years [19]. The optimal treatment of patients with rising PSA (biochemical recurrence) after radical prostatectomy (salvage treatment) or treatment of patients who are at high risk for relapse based on histologic features (adjuvant treatment) is uncertain [20]. Analysis of previously performed studies as well as future studies may help to resolve these issues. 

One study involving men with node-positive prostate cancer (T1 or T2 N1M0) demonstrated that early adjuvant ADT (GnRH agonist/orchiectomy) after radical prostatectomy and lymphadenectomy significantly improved all-cause (P = 0.02) and cause-specific (P < 0.01) survival compared with delayed treatment [16]. Bolla et al noted that patients with high-risk, locally advanced disease (T3 or T4 N0M0 or T1-T2 N1M0) treated with a GnRH agonist started during EBRT and continuing for 3 years also significantly improved all-cause (P = 0.0002) and cause-specific (P = 0.0001) survival compared with EBRT alone [17]. 

Updated results of the phase 3 Radiation Therapy Oncology Group 85-31 trial evaluating the potential benefit of ADT following standard EBRT for disease in patients with an unfavorable prognosis demonstrated that ADT in addition to definitive EBRT resulted in highly significant improvement in local control, freedom from distant metastases, and biochemical-free survival [21]. Furthermore, the Agency for Health Care Research and Quality (formerly the Agency for Health Care Policy and Research) performed a systematic review of the available randomized clinical trial evidence comparing EBRT with EBRT and prolonged ADT. The review found a difference in 5-year overall survival in favor of EBRT plus ADT using a GnRH agonist or orchiectomy compared with EBRT alone (hazard ratio {HR}, 0.631; 95% confidence interval {CI}: 0.479-0.831) [22].

Sasse and colleagues analyzed data from 10 trials published from 1988 to 2011 (6555 patients) and reported a statistically significant advantage with the use of ADT in terms of overall and disease-free survival compared with EBRT alone [23]. Long-term goserelin (up to 3 years) provided the higher magnitude of clinical benefit. There were no trials evaluating other forms of GnRH agonist/antagonist as monotherapy. Additionally, a Cochrane review evaluating hormone therapy for localized and locally advanced prostate cancer concluded that ADT combined with either prostatectomy or EBRT is associated with significant clinical benefits [24]. Significant long-term control may be achieved when administered prior to prostatectomy or EBRT, which may improve patient QOL. However, these disease-related benefits are associated with significant side effects as well as cost. The optimal duration of ADT treatment remains to be determined. 

Adverse Events and the Emergence of CRPC

The main limitations of ADT include the common side effects of this type of treatment, as well as potential for the emergence of CRPC (androgen-insensitive prostate cancer) when ADT is used long term. In October 2010, the FDA announced that the prescribing information for a GnRH agonist/antagonist would include new warnings on the increased risk for heart disease and diabetes [25].

Major Adverse Effects of ADT

The incidence of some of the adverse effects of ADT is shown in Table 2 [26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49]. Common side effects include skeletal-related complications, metabolic and cardiovascular complications, sexual dysfunction, hot flashes, periodontal disease, cognitive effects, and mood disorders [50-56]. Androgen deprivation therapy decreases bone mineral density, which may lead to an increased risk for skeletal fracture [55,57,58]. The risk may be further compounded by preexisting bone mineral density loss. Lifestyle modifications and other treatments are available to prevent and mitigate bone-related complications in men on ADT. Lifestyle modifications include: smoking cessation, decreased alcohol intake, weight-bearing exercise, and calcium and vitamin D supplementation. 

Zoledronate has been shown to increase bone density in men on ADT [59]. Pamidronate in combination with leuprolide acetate preserved bone density in a small study of men with prostate cancer on leuprolide acetate ADT [60]. Although these and other bisphosphonates have been shown to be effective in preventing bone loss based on bone marrow density studies, most studies have been underpowered and of too short a duration to address fracture issues. 

Denosumab was shown to be effective in bone loss prevention as well as reductions in new osteoporotic fractures in a double-blind, multicenter, 3-year study [61]. Compared with the placebo group, the denosumab group showed significant increases in bone marrow density as early as 1 month and sustained through 36 months. Patients who received denosumab also showed a decreased incidence of new vertebral fractures at 36 months (1.5% vs. 3.9% with placebo, P = 0.006). Rates of adverse events were similar between the groups. Because denosumab can cause hypocalcemia, vitamin D supplementation may be necessary. Other side effects include fatigue, decreased phosphate levels, and nausea [62].

In a review of major AEs associated with ADT in men with prostate cancer, Taylor et al found only 3 studies that met inclusion criteria and investigated diabetes and cardiovascular morbidity secondary to ADT treatment [39]. Using retrospective cohort study designs, all 3 studies reported a significantly increased risk for diabetes (36% to 49%) or cardiovascular morbidity after the start of ADT [34,35,63]. 

Specifically, Lage and colleagues followed patients for up to 18 months after the start of ADT and noted a significant increase in the risk for diabetes after adjustment for covariates (treatment for 12 months: relative risk {RR}, 1.36; 95% CI, 1.07-1.74; treatment for 18 months: RR, 1.49; 95% CI, 1.12-1.99) [63]. In a retrospective cohort study of a population-based registry, Saigal and colleagues noted that men who underwent ADT had a 20% increased risk for cardiovascular morbidity compared with men who did not undergo ADT. Increased risk for cardiac morbidity was observed within the first 12 months of treatment [35]. For men with metastatic disease, efforts to reduce cardiac risk factors through diet, exercise, or the use of lipid-lowering agents may mitigate some of the risks of ADT. 

Sexual dysfunction (lack of desire, erectile dysfunction) and hot flashes are common side effects of ADT. A variety of therapies have been used for the management of sexual dysfunction and hot flashes (Table 3) [64].

The Emergence of CRPC

Long-term exposure to ADT may lead to resistance, which can result in CRPC, which is defined as 3 consecutive rises in serum PSA of ≥ 10% each after nadir has been reached, castrate levels of serum testosterone (< 50 ng/dL, ideally < 20 ng/mL), and a trial of antiandrogen therapy [65]. In patients on ADT with bone metastases, the median time to symptomatic progression after a rise in PSA level of > 4 ng/mL is approximately 6 to 12 months, with a median time to death of 18 months [66]. Once the patient exhibits symptoms, median survival historically has been approximately 1 year in untreated patients. Fortunately, the advent of new therapeutic options for CRPC has led to significant improvements in survival. Typically, if patients are not responding to therapy with a GnRH agonist/antagonist, an antiandrogen is added.

In practice, serum testosterone levels should be checked in men with increasing PSA levels while receiving a GnRH agonist/antagonist. Based on those results, the GnRH could be changed; surgical castration could be considered with a noncastrate testosterone level > 50 ng/mL. If a castrate testosterone level is observed, an antiandrogen can be added for combination ADT (CADT). The rational for CADT is that androgen production arises from both testicular and adrenal sources, but the GnRH agonist/antagonist affects only the testicular production. Combination therapy would affect the production of testosterone as well as its action. 

Studies have shown mixed results of the impact of CADT. Initial studies suggested that there was a benefit to CADT on both duration of response and survival [67]. Three large studies demonstrated a survival advantage to use of CADT [68-70]; however, the Prostate Cancer Trialists’ Collaborative Group failed to show such an advantage [71]. A Cochrane analysis of combination therapy showed variable results, depending on the study [72]. A comparison of results found with monotherapy versus combination therapy is shown in Table 4 [68,69,70,71,72].

Decreasing Morbidity and Resistance to ADT: The Role of Intermittent ADT

Typically administered on a continuous basis, ADT can be associated with significant morbidity and eventual progression of disease. Efforts to improve morbidity while maintaining efficacy have led to the technique of intermittent ADT (IADT). Guidelines for IADT vary, but the concept is the continuous administration of ADT for a certain time period to sufficiently lower the PSA, followed by a period of cessation of ADT when the PSA rises over time to a predefined level, at which time ADT is resumed (Figure 1 and Figure 2) [73]. Figure 1 is an algorithm for the patient on CADT for decision to start a nontreatment cycle of IADT (i.e., the patient has been on CADT for a defined period of time/PSA nadir, which in this algorithm is 8 months) and is ready to be evaluated for IADT. Figure 2 illustrates a suggested management algorithm for the patient who is in the nontreatment cycle of IADT. These on- and off-treatment cycles are continued until ADT resistance emerges. The goal of IADT is to maintain disease control, but also to allow for periods of time off ADT to decrease morbidity and improve QOL. Studies examining efficacy of IADT and ADT, effects of ADT on QOL, effects of IADT on morbidity and QOL, and duration of response to IADT are reviewed below. 

Clinical Trial Findings With IADT

Several studies on the effects on IADT compared with CADT have been conducted. So-Rosillo et al evaluated the use of IADT in 43 men with nonmetastatic, progressive noncastrate prostate cancer treated with IADT: 21 men had received no prior primary therapy and 22 had developed recurrent disease after previous local therapy [74]. Treatment included use of CADT in 32 men and use of monotherapy (a GnRH agonist) in 11 men. Patients were allowed to stop ADT when: (a) PSA became undetectable, (b) after 9 to 12 months of ADT, or (c) at the patient’s request. Progressive disease and androgen independence were defined by rising PSA despite ADT. Follow-up ranged from 18 to 153 months (median, 68.2 months) from the start of treatment.

Patients spent an average of 50.7% of the time on ADT and 49.3% off ADT. Eleven men developed androgen-independent progressive disease, with a median time to progression of 47 months. Investigators could not identify any potential risk factors for development [74].

Klotz and colleagues conducted a phase 3, open-label, randomized noninferiority trial of IADT versus CADT for PSA progression after radical therapy [75]. Eligible patients had rising PSA > 3.0 ng/mL more than 1 year post radical therapy or salvage EBRT with or without up to 1 year of neoadjuvant ADT for localized disease. Stratification factors included time since EBRT (> 1 to 3 years vs. > 3 years), initial PSA (< 15 vs. > 15 ng/mL), and prior radical prostatectomy or ADT. The primary end point was overall survival; secondary end points included QOL, heart rate, cholesterol levels (total, high-density lipoprotein, low-density lipoprotein), length of nontreatment periods, testosterone and potency recovery. 

In this study, median overall survival was 8.8 versus 9.1 years on IADT and CADT, respectively (HR: 1.02; 95% CI: 0.86 to 1.21; P for noninferiority {HR, IADT vs. CADT: ≥ 1.25} 0.009). Time to hormone refractory status was statistically significantly improved in the IADT arm (HR: 0.80; 95% CI: 0.67-0.98; P = 0.024). Other than reduced hot flashes in patients randomized to IADT, there was no difference in AEs for IADT versus CADT, including myocardial events or osteoporotic fractures [75].

Miller at al. performed a multicenter, randomized, 2-arm study comparing treatment with intermittent goserelin plus bicalutamide versus continuous goserelin plus bicalutamide [76]. The primary endpoint was time to clinical and/or biochemical progression despite androgen suppression. Secondary endpoints were survival time, QOL, and toxicity. After the induction phase of 24 weeks with combined androgen blockade, 335 patients whose PSA decreased < 4 ng/mL or + 90% from baseline were randomized. Approximately two-thirds of patients in both the IADT and CADT arms (65% vs. 66%, respectively) experienced a clinical and/or biochemical progression during the study. The median time to progression was longer for patients on IADT compared with CADT (16.6 months vs. 11.5 months, respectively); however, the difference was not statistically significant (P = 0.1758). The median time to death from any cause was 52.4 months in the IADT group compared to 53.8 months in the CADT arm (P = 0.658). Patient self-assessment of overall health and sexual activity appeared to be more favorable in the IADT arm compared with the CADT arm [76].

Investigators have also explored the role of IADT in patients with CRPC. (Note that in patients with CRPC, ADT is continued while patients undergo additional therapy, such as chemotherapy.) Organ and colleagues conducted a multicenter randomized trial to compare IADT with CADT in patients with CRPC [77]. Patients were randomized 1:2 to CADT or IADT with a GnRH agonist, and were followed every 2 months with clinical assessments, laboratory evaluations, and QOL questionnaires. If the serum testosterone level increased above castrate levels (1.75 nmol/L), the GnRH agonist was resumed. The primary endpoints were overall survival, health-related QOL, and cost. 

In total, 31 patients were followed for a median of 26.8 months. Time to resuming ADT in the IADT arm was a median of 17.9 months. There was no difference in overall or cancer-specific survival or QOL between the IADT and CADT arms at 0 and 12 months; however, the total mean costs at 24 months were significantly lower in the IADT arm [77].

Factors Predicting Response to IADT

Several studies have assessed whether certain factors can predict response to IADT. Howlader and colleagues found that a shorter PSA doubling time during the first or last “off treatment” cycle of IADT was associated with a shorter time to development of CRPC in patients who were treated for biochemical relapse after primary radical prostatectomy or EBRT [78]. Keizman and colleagues noted that pre-treatment PSA doubling time (> 6 vs. < 6), first off-treatment interval PSA doubling time (≥ 3 vs. < 3), and PSA nadir during the first treatment interval (< 0.1 vs. > 0.1) were associated with disease progression [79].

In a study by Strum et al, PSA measurement 1 month after CADT and slow testosterone recovery off CADT were associated with prolonged time off CADT [80]. Chaudhary and colleagues noted that with each consecutive cycle of IADT, there appeared to be a progressive decrease in the time off ADT, despite achieving a low nadir PSA [81]. Lastly, Scholz and colleagues reviewed responses on IADT for the first and subsequent cycle of IADT, and found that, compared with patients who successfully reached undetectable PSA on the second cycle, those failing the second cycle had a significantly lower mean baseline testosterone (387 ng/mL vs. 481 ng/mL, P < 0.001), predominantly clinical stage D disease (4/6 patients vs. 3/25 patients, chi-square = 132, P < 0.001), and a longer time to reach undetectable PSA (median 4.5 months vs. 8.0 months, P = 0.072) [82].

Effects of IADT on Morbidity and QOL

The potential for decreased morbidity and improved QOL were the impetus for consideration of IADT in the management of advanced prostate cancer. Machado and colleagues evaluated the natural history of bone mineral density in patients receiving CADT versus IADT, and noted that CADT induced 50% of the patients to a sustained bone disorder. In the IADT patients who developed osteoporosis after initial administration of ADT (50%), 70% could migrate to osteopenia or normal scan during follow-up (P < 0.05) [83]. In a randomized international phase 3 trial comparing IADT with CADT in men with an increasing PSA > 3.0 ng/mL more than 1 year after radical therapy or salvage radiotherapy with or without up to 1 year of neoadjuvant ADT completed 12 months prior to randomization, IADT was noted to improve several global QOL measures, including physical function (P < 0.01), fatigue (P < 0.01), urinary problems (P = 0.01), hot flashes (P < 0.01), desire for sexuality (P < 0.01), and erectile function (P < 0.01) [73].

CONCLUSION

Androgen deprivation therapy remains the first-line therapy for advanced prostate cancer. Although initially used in men with metastatic prostate cancer, it is more frequently used in men with biochemical recurrence. The role of CADT in the treatment of advanced prostate cancer is controversial; however, it is often employed in men failing GnRH agonist/antagonist monotherapy. ADT is associated with significant side effects, some of which may develop as early as 3 months on therapy, and long-term use is associated with the emergence of CRPC. Thus, investigators have sought ways to decrease the risk of side effects and the emergence of CRPC without affecting survival. Intermittent use of ADT has yielded comparable survival rates compared with continuous ADT, while improving QOL in men with advanced prostate cancer in a variety of settings.

To Receive CME Credit

To complete the post-test and evaluation for this activity and receive CME credit, click here.

REFRENCES

  1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012.
  2. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations), Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to SEER Web site, April 2012. Accessed April 30, 2012.
  3. Etzioni R, Tsodikov A, Mariotto A, et al. Quantifying the role of PSA screening in the US prostate cancer mortality decline. Cancer Causes Control. 2008;19(2):175-181.
  4. Cetin K, Beebe-Dimmer JL, Fryzek JP, Markus R, Carducci MA. Recent time trends in the epidemiology of stage IV prostate cancer in the United States: analysis of data from the Surveillance, Epidemiology, and End Results Program. Urology. 2010;75(6):1396-1404.
  5. Moul JW, Wu H, Sun L, et al. Epidemiology of radical prostatectomy for localized prostate cancer in the era of prostate-specific antigen: an overview of the Department of Defense Center for Prostate Disease Research National Database. Surgery. 2002;132(2):213-219.
  6. Moul JW, Wu, Sun L, et al. Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. J Urol. 2004;171(3):1141-1147.
  7. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin. 2004;54(1):8-29.
  8. Moul JW. Prostate specific antigen only progression of prostate cancer. J Urol. 2000;163(6):1632-1642.
  9. Djavan B, Moul JW, Zlotta A, Remzi M, Ravery V. PSA progression following radical prostatectomy and radiation therapy: new standards in the new millennium. Eur Urol. 2003;43(1):12-27. 
  10. Moul JW. The evolving definition of advanced prostate cancer. Rev Urol. 2004;6(suppl 8):s10-s17. 
  11. Moul JW. Treatment of metastatic prostate cancer. Braz J Urol. 2000;26(2):132-145. 
  12. D’Amico AV, Moul J, Carroll PR, et al. Cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific-antigen era. J Clin Oncol. 2003;21(11):2163-2172. 
  13. Marks LS. Luteinizing hormone-releasing hormone agonists in the treatment of men with prostate cancer: timing, alternatives, and the 1-year implant (review). Urology. 2003;62(6 suppl 1):36-42. 
  14. Seidenfeld J, Samson DJ, Hasselblad V, et al. Single-therapy androgen suppression in mend with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med. 2000;132(7):566-577. 
  15. Shahinian VB, Kuo YF, Freeman JL, Orihuela R, Goodwin JS. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate cancer. Cancer. 2005;103(8):1615-1624. 
  16. Messing EM, Mamola J, Sarosdy M, et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node positive prostate cancer. N Engl J Med. 1999;341:1782-1788.
  17. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC Study): a phase III randomized trial. Lancet. 2002;360(9327):103-108. 
  18. Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostate cancer: initial results of the Medical Research Council trial. Br J Urol. 1997;79(2):235-246. 
  19. Anscher MS, Prosnitz LR. Multivariate analysis of factors predicting local relapse after radical prostatectomy—possible indications for postoperative radiotherapy. Int J Radiat Oncol Biol Phys. 1991;21(4):941-947. 
  20. Pound CR, Partin AW, Eisenberger MA et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:1591-1597. 
  21. Lawton CA, Winter K, Murray K, et al. Updated results of the phase III radiation therapy oncology group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 2001;49(4):937-946. 
  22. Seidenfeld J, Samson DJ, Aronson N, et al. Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostate cancer. Evid Rep Technol Assess (Summ). 1999;(4):i-x, 1-246, I1-36, passim.
  23. Sasse AD, Sasse E, Carvalho AM, Macedo LT. Androgenic suppression combined with radiotherapy for the treatment of prostate adenocarcinoma: a systematic review. BMC Cancer. 2012;12:54.
  24. Kumar S, Shelly M, Harrison C, Coles B, Wilt TJ, Mason MD. Neoadjuvant and adjuvant hormone therapy for localized and locally advanced prostate cancer (review). Cochrane Database Syst Rev. 2006;(4):CD006019. 
  25. US Food & Drug Administration. FDA: Include warnings on risk for class of prostate cancer drugs (press release). October 20, 2010. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230334.htm. Accessed April 19, 2012. 
  26. Smith MR, Finkelstein JS, McGovern FJ, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab. 2002;87:599-603. 
  27. Smith MR. Changes in fat and lean body mass during androgen-deprivation therapy for prostate cancer. Urology. 2004;63:741-745. 
  28. Smith MR, Lee H, McGovern F, et al. Metabolic changes during gonadotropin-releasing hormone agonist therapy for prostate cancer: differences from the classic metabolic syndrome. Cancer. 2008;112:2188-2194. 
  29. Dockery F, Bulpitt CJ, Agarwal S et al. Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinemia. Clin Sci (Lond). 2003;104:195-201. 
  30. Eri LM, Urdal P, Bechensteen AG. Effects of the luteinizing hormone-releasing hormone agonist leuprolide on lipoproteins, fibrinogen, plasminogen activator inhibitor in patients with benign prostatic hyperplasia. J Urol. 1995;154:100-104. 
  31. Saylor PJ, Smith MR. Androgen deprivation therapy: defining the problem and promoting health among men with prostate cancer. J Natl Compr Canc Netw. 2010;8(2):211-223. 
  32. Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab. 2006;91:1305-1308. 
  33. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2009;32(suppl 1):S62-S67. 
  34. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24:4448-4456. 
  35. Saigal CS, Gore JL, Krupski TL, et al. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer. 2007;110(7):1493-1500. 
  36. Efstathiou JA, Bae K, Speight J, et al. Cardiovascular mortality and duration of androgen deprivation for locally advanced prostate cancer: analysis of RTOG 92-02. Eur Urol. 2008;54:816-823. 
  37. Roach M III, Bae K, Speight J, et al. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long term results of RTOG 8610. J Clin Oncol. 2008;26:585-591. 
  38. Efstathiou JA, Bae K, Shipley WU, et al. Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31. J Clin Oncol. 2009;27:92-99. 
  39. Taylor LG, Canfield SE, Du XL. Review of major adverse effects of androgen-deprivation therapy in men with prostate cancer. Cancer. 2009;115(11):2388-2399. 
  40. Smith MR, McGovern FJ, Zeitman AL, et al. Pamidronate to prevent bone loss in men receiving gonadotropin releasing hormone agonist therapy for prostate cancer. N Engl J Med. 2001;23:7897-7903. 
  41. Diamond TH, Winters J, Smith A et al. The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade: a double blind, randomized, placebo-controlled crossover study. Cancer. 2001;92:1444-1450. 
  42. Smith MR, Eastham J, Gleason D et al. Randomized controlled trial of zoledronic acid to prevent bone loss in men undergoing androgen deprivation therapy for nonmetastatic prostate cancer. J Urol. 2003;169:2008-2012.
  43. Michaelson MD, Kaugman DS, Lee H et al. Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol. 2007;25:1038-1042. 
  44. Greenspan SL, Nelson JB, Trump DL, Resnick NM. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial. Ann Intern Med. 2007;146:416-424. 
  45. Izumi K, Mizokami A, Sugimoto K et al. Risedronate recovers bone loss in patients with prostate cancer undergoing androgen-deprivation therapy. Urology. 2009;73:1342-1346. 
  46. Saad F, Smith MR, Egerdie B, et al. Denosumab for prevention of fracture in men receiving androgen deprivation therapy (ADT) for prostate cancer PC). Presented at: American Society of Clinical Oncology 45th Annual Meeting; May 29-June 2, 2009; Orlando FL. Abstract 5056. 
  47. Smith MR, Morton RA, Malkowicz B, et al. A phase III randomized controlled trial of toremifene to prevent fractures and other adverse effects of androgen deprivation therapy in men with prostate cancer. Presented at: American Association for Cancer Research Annual Meeting; April 18-22, 2009; Denver, CO. 
  48. Watts NB, Lewiecki EM, Miller PD, Baim S. National Osteoporosis Foundation 2008 Clinician's Guide to Prevention and Treatment of Osteoporosis and the World Health Organization Fracture Risk Assessment Tool (FRAX): what they mean to the bone densitometrist and bone technologist. J Clin Densitom. 2008;11:473-477.
  49. Autorino R, Perdona S, D’Armiento M, et al. Gynecomastia in patients with prostate cancer: update on treatment options. http://www.ncbi.nlm.nih.gov/pubmed/16432533. Gynecomastia in patients with prostate cancer: update on treatment options. Prostate Cancer Prostatic Dis. 2006;9(2):109-114. 
  50. Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer (review). JAMA. 2005;294(2):238-244. 
  51. Green HJ, Pakenham KI, Headley BC, et al. Quality of life compared during pharmacological treatments and clinical monitoring for non-localized prostate cancer: a randomized controlled trial. BJU Int. 2004;93(7):975-979. 
  52. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of the “androgen deprivation syndrome” in men receiving androgen deprivation for prostate cancer. Arch Intern Med. 2006;166(4):465-471. 
  53. Famili P, Cauley JA, Greensplan SI. The effect of androgen deprivation therapy on periodontal disease in men with prostate cancer. J Urol. 2007;177(3):921-924. 
  54. Guise TA, Oefelein MG, Eastham JA, Cookson MS, Higano CS, Smith MR. Estrogenic side effects of androgen deprivation therapy. Rev Urol. 2007;9(4):163-180. 
  55. Alibhai SM, Gogov S, Alibhai Z. Long-term side effects of androgen deprivation therapy in men with non-metastatic prostate cancer: a systematic literature review. Crit Rev Oncol Hematol. 2006;60(3):201-215.
  56. Shahani S, Braga-Basaria M, Basaria S. Androgen deprivation therapy in prostate cancer and metabolic risk for atherosclerosis. J Clin Endocrin Metab. 2008;93(6):2042-2049. 
  57. Kiratli BJ, Srinivas S, Perkash I, Terris MK. Progressive decrease in bone density over 10 years of androgen deprivation therapy in patients with prostate cancer. Urology. 2001;57(1):127-132. 
  58. Preston DM, Torréns JI, Harding P, Howard RS, Duncan WE, McLeod DG. Androgen deprivation in men with prostate cancer is associated with an increased rate of bone loss. Prostate Cancer Prostatic Dis. 2002;5(4):304-310. 
  59. Campbell SC, Bhoopalam N, Moritz TE, et al. The use of zoledronic acid in men receiving androgen deprivation therapy for prostate cancer with severe osteopenia or osteoporosis. Urology. 2010;75(5):1138-1143. 
  60. Smith MR, McGovern FJ, Zietman AL, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med. 2001;345(13):948-955. 
  61. Smith MR, Egerdie B, Toriz NH, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361(8):745-755. 
  62. Denosumab [prescribing information]. Thousand Oaks, CA: Amgen Inc; 2011. 
  63. Lage MJ, Barber BL, Markus RA. Association between androgen-deprivation therapy and incidence of diabetes among males with prostate cancer. Urology. 2007;70(6):1104-1108. 
  64. Ellsworth P. 100 Q&A About Prostate Cancer. 2nd ed. Sudbury, MA: Jones and Bartlett Publishers; 2009.
  65. Scher HI, Halabi S, Tannock I, et al; Prostate Cancer Clinical Trials Working Group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26(7):1148-1159.
  66. Terris MK, Qureshi SM, Rhee A. Prostate cancer – metastatic and advanced prostate cancer. http://emedicine.medscape.com/article/454114. Updated June 22, 2011. Accessed June 27, 2011. 
  67. Labrie F, Belanger A, Cusan L, et al. History of LHRH agonist and combination therapy in prostate cancer. Endocr Relat Cancer. 1996;3:243-278.
  68. Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989;321:419-424.
  69. Denis LJ, Carneiro de Moura JL, Bono A, et al. Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III EORTC trial (30853). EORTC GU Group and EORTC Data Center. Urology. 1993;42(2):119-130.
  70. Janknegt RA, Abbou CC, Bartoletti R, et al. Orchiectomy and nilutamide or placebo as treatment of metastatic prostate cancer in a multinational double-blind randomized trial. J Urol. 1993;149(1):77-83.
  71. Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomized trials. Lancet. 2000;355(9214):1491-1498 
  72. Schmitt B, Bennet C, Seidenfeld J, Samdson D, Wilt T. Maximal androgen blockade for advanced prostate cancer (review). Cochrane Database Syst Rev. 2000;(2):CD001526.
  73. Crook JM, O'Callaghan CJ, Ding K, et al. A phase III randomized trial of intermittent versus continuous androgen suppression for PSA progression after radical therapy. Presented at: 2011 American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, IL. Abstract 4514.
  74. So-Rosillo R, Small EJ, Weinberg V. Intermittent androgen deprivation therapy (ADT) for patients with nonmetastatic prostate cancer: a retrospective review (abstract). J Clin Oncol. 2007;25(18S, Pt I):15635.
  75. Klotz L, O’Callaghan CJ, Ding K, et al. A phase III randomized trial comparing intermittent versus continuous androgen suppression for patients with PSA progression after radical therapy NCIC CTGPR.7/SWOG JPR.7/CTSU JPR.7/UK Intercontinental Trial CRUKE/01/013. Presented at: American Society of Clinical Oncology – Genitourinary Cancer Symposium 2011, February 17-19, 2011; Orlando, FL. Abstract 3.
  76. Miller K, Steiner U, Lingrau A, et al. Randomised prospective study of intermittent versus continuous androgen suppression in advanced prostate cancer (abstract). J Clin Oncol. 2007;25(18S):5015.
  77. Organ M, Wood L, Wilke D, et al. Intermittent androgen-deprivation therapy in the management of castrate-resistant prostate cancer (CRPCa): results of a multi-institutional randomized prospective clinical trial (abstract). J Clin Oncol. 2011;29:(suppl 7):abstract 131. 
  78. Howlader N, Tam S, Etzioni R, Higan CS. PSA doubling time (PSA-DT) during the “off treatment” interval in men with biochemical relapse of prostate cancer treated with intermittent androgen suppression (IAS) (abstract). J Clin Oncol. 2005;23(16S, Pt I):4670.
  79. Keizman D, Huang P, Antonarakis ES, et al. The change of PSA doubling time and its association with disease progression in patients with biochemically relapsed prostate cancer treated with intermittent androgen deprivation. Prostate. 2011;71(15):1608-1615.
  80. Strum SB, Scholz MC. Intermittent hormone blockade (IHB): Optimal induction duration and predictive factors for prolonged time off hormone blockade (HB). Presented at: American Society of Clinical Oncology 34th Annual Meeting; May 17-19, 1998; Los Angeles, CA. Abstract 1204.
  81. Chaudhary, Grossfeld G, Reese D, Carroll P, Small E. Intermittent androgen deprivation (IAD): Patterns of failure in clinically localized prostate cancer (PCA). Presented at: American Society of Clinical Oncology 36th Annual Meeting; May 20-24, 2000; New Orleans, LA. Abstract 1309.
  82. Scholz M, Stru S, Madgen L, McDermed J. Intermittent androgen deprivation (IAD) therapy for prostate cancer (PC): PSA response on cycle 1 (C1) can predict response on subsequent cycle (abstract). Presented at: American Society of Clinical Oncology 35th Annual Meeting; May 15-18, 1999; Philadelphia, PA. Abstract 1359.
  83. Machado MT, Wroclawski ER, del Giglio A. Natural history of bone loss induced by androgen deprivation in hormone sensitive prostate cancer patients: A prospective comparison between continuous and intermittent therapy. Presented at: American Society of Clinical Oncology – Prostate Cancer Symposium 2006; February 24-26, 2006; San Francisco, CA. Abstract 188.