US Pharm. 2009;34(8):HS-15-HS-18.
Cancer is the cause of death of one in every four U.S. residents.1 The primary site of cancer among men is the prostate, accounting for 25% of cancer cases in males.1 Men aged 60 years and older constitute the age group primarily affected by prostate cancer.1 African American men have a higher risk of prostate cancer and of death due to prostate cancer than men of other races.1
From the late 1980s to the mid-1990s, there was a rapid increase in the incidence of prostate cancer.1,2 In the last decade, prostate cancer incidence has stabilized and death rates have declined.1 These trends are likely the result of prostate-specific antigen (PSA) screening and early-stage prostate cancer detection and treatment.1,2
Pathophysiology
The prostate requires stimulation from androgens for normal growth and function. The hypothalamus is responsible for producing gonadotropin-releasing hormone, also known as luteinizing hormone (LH)-releasing hormone (LHRH). Pulsatile release of LHRH results in the release of follicle-stimulating hormone (FSH) and LH from the pituitary gland, whereas continuous release of LHRH results in the suppression of FSH and LH release.3 LH causes the Leydig cells in the testes to produce the androgen testosterone, which is converted to dihydrotestosterone (DHT) by 5-alpha reductase, or 5-AR (FIGURE 1). DHT has a greater affinity than testosterone for prostate androgen receptors. Growth factors and cellular signaling resulting from DHT stimulation are thought to cause progression to prostate cancer.4
Screening
Screening for prostate cancer continues to be a topic of debate. The New England Journal of Medicine recently published two studies that yielded discordant results regarding the impact of early PSA screening on mortality.5,6 Controversy lies in the concern that prostate cancer could be overdiagnosed and overtreated for marginal mortality benefits. The American Urological Association (AUA) now recommends that screening for prostate cancer, using PSA and digital rectal examination (DRE), be started at age 40.7 The goal for screening, according to the AUA, is reduced morbidity and mortality and reduced metastasis at the expense of overdiagnosis and overtreatment of prostate cancer.7 Other guidelines recommend that screening begin at age 50 in most patients.7
Prevention
Investigations into the effects of antioxidants on prostate cancer prevention have had mixed results, but a recent study evaluating vitamins C and E that enrolled more than 14,000 physicians and involved 8 years of follow-up suggests that these substances have no effect.8 Guidelines published in 2009 by the AUA and the American Society of Clinical Oncology (ASCO) state that the use of 5-AR inhibitors might prevent the development of prostate cancer.9 However, patients who are treated with 5-AR inhibitors may develop a higher-grade prostate cancer compared with patients not treated with 5-AR inhibitors.9
Treatment
Drug Class Review: The LHRH analogues (or agonists) leuprolide, goserelin, and histrelin exert their pharmacologic effect by acting as potent inhibitors of pituitary gonadotropin secretion. The initial administration of these medications results in an increase in serum LH and FSH and, subsequently, an initial surge in serum testosterone and DHT levels in males. This can cause a worsening of symptoms such as urinary obstruction and bone pain. Chronic administration of the biodegradable formulations of these medications results in suppression of serum testosterone levels equal to levels seen in surgically castrated men after 2 to 4 weeks of therapy. The reduction in testosterone levels is reversible upon discontinuation of the medication.10,11
LHRH agonists are the mainstay of therapy and are approved as monotherapy for palliative treatment of advanced prostate cancer, but they are not without risks. The major side effects associated with this class of medication are increased hot flashes, decreased sexual function or libido, peripheral edema, osteoporosis, and cardiovascular events.10, 11
The nonsteroidal antiandrogens bicalutamide, flutamide, and nilutamide work by binding to androgen receptors in the tissues and preventing androgens from binding to their target. This is effective in androgen-dependent prostate carcinomas and has no impact on decreasing serum testosterone levels.12 The side effects associated with this class of medications include hot flashes, gynecomastia, and anemia.12 These medications are approved only as combination therapy with LHRH agonists to treat prostate cancer; they are not approved as monotherapy.12
Recently approved, degarelix is the only member of the LHRH antagonist class. This medication works by immediately and reversibly binding to pituitary gonadotropin receptors, suppressing androgen production and reducing serum testosterone levels without the initial testosterone surge that occurs with LHRH agonists. The most common adverse reactions associated with degarelix are injection-site reactions, hot flashes, weight gain, and increased liver enzymes.13 Degarelix is currently indicated for treatment of advanced prostate cancer.13
Active Surveillance: Patients with localized prostate cancer may be candidates for active surveillance. This strategy involves DRE and PSA evaluation every 6 to 12 months, periodic needle biopsy, and withholding of pharmacologic, radiotherapeutic, and surgical intervention. Advantages include avoidance of adverse drug events of therapy and maintenance of quality of life; progression to incurable cancer and anxiety associated with untreated cancer are two of the disadvantages.2
Hormonal Monotherapy: The standard treatment for advanced prostate cancer is androgen deprivation therapy (ADT).14,15 ADT can be either surgical castration via bilateral orchiectomy or medical castration via LHRH agonists or antagonists.14 LHRH agonists have been a mainstay of therapy for advanced prostate cancer since they demonstrated an efficacy similar to that for surgical castration. Benefits of LHRH agonist therapy include long-term reductions in bone pain, spinal-cord compression, and urinary obstruction.16 Given the limited comparative data available, similar efficacy among the many existing formulations of LHRH agonists is assumed.
Hormonal therapy is more controversial as a primary therapy for localized prostate cancer than for advanced prostate cancer. Use in localized prostate cancer is increasing despite a paucity of randomized, controlled trials.17 A cohort study concluded that 10-year survival was not affected by ADT use in patients with localized prostate cancer, but that minimal improvement may exist for patients at higher risk for disease progression.18 A meta-analysis evaluating timing of administration of adjunctive LHRH agonists in patients with locally advanced prostate cancer concluded that early administration of ADT resulted in reduced mortality and delayed disease progression.19
Because of the adverse effects associated with LHRH agonist therapy, a careful risk-versus-benefit analysis must take place. In addition to being counseled about adverse effects, patients should be screened for diabetes, cardiovascular disease, and fracture risk.2 Risk of fracture can be evaluated with the FRAX algorithm developed by the World Health Organization.2,20 Zoledronic acid and alendronate are recommended for patients with an elevated risk of fracture who are receiving ADT.
The primary benefit of degarelix therapy is avoidance of the testosterone surge associated with LHRH agonist monotherapy.21 A phase III, open-label, noninferiority trial compared degarelix with monthly injections of leuprolide with or without bicalutamide in patients with localized, locally advanced, or metastatic cancer.21 Degarelix was found to be noninferior to leuprolide with respect to suppression of testosterone to 0.5 ng/mL over 1 year. Adverse effects associated with degarelix included local site reactions (occurring in 40% of patients vs. <1% in the leuprolide group) and chills; arthralgia and urinary tract infections were more common in patients randomized to leuprolide.21 If the literature continues to suggest that degarelix is not associated with systemic allergic reactions, this drug might be a first-line option, especially for patients at high risk for symptomatic testosterone surge (e.g., those with urethral obstruction or spinal-cord compression).
Combined Androgen Blockade (CAB): Given adjunctively with LHRH agonists, nonsteroidal antiandrogens can prevent the surge phenomenon during the first 2 to 3 weeks of hormonal therapy.22 Both the 2009 National Comprehensive Cancer Network (NCCN) practice guidelines and the 2004 ASCO guidelines recommend administering an antiandrogen before or during the first weeks of LHRH agonist therapy in prostate cancer patients with overt metastases who are at risk for experiencing a testosterone surge.2,22
Although castration causes testicular androgens to be suppressed, androgens of the adrenal gland still can become incorporated into the cell nucleus.14 The rationale behind chronic CAB is to eliminate androgen action by adding a nonsteroidal antiandrogen to castration.15
The concept of CAB evolved in 1985.15 Since then, about 30 randomized, prospective trials have been conducted, but only a few of them have shown an advantage of CAB over castration.15 The 2007 update of the ASCO guidelines recommends medical or surgical castration monotherapy as first-line treatment for patients with metastatic prostate cancer, but advises consideration of CAB.23 These recommendations are based on the results of two recent studies specifically examining the use of bicalutamide CAB.23 The studies suggested that bicalutamide CAB may increase overall survival in patients with recurrent or metastatic androgen-sensitive prostate cancer and may cause a minimal increase in adverse effects compared with castration alone.23 Therefore, these guidelines recommend considering bicalutamide CAB in this patient population until further studies address this potential survival benefit.23
The 2009 NCCN practice guidelines state that CAB provides no additional benefit over medical or surgical castration alone in patients with metastatic prostate cancer.2 A relatively large, prospective, double-blind trial exemplifies this view.14 This trial evaluated the overall survival of almost 1,400 metastatic prostate cancer patients who underwent bilateral orchiectomy and were randomized to receive either flutamide or placebo.14 Patients in the CAB arm did not experience increased survival compared with the placebo arm; CAB patients also had higher rates of diarrhea and anemia.14 The NCCN guidelines go on to state, however, that patients not achieving adequate testosterone suppression (serum testosterone <50 ng/mL) are an exception and that additional hormonal manipulations such as CAB may be considered even though the benefits of CAB are not clear.2
Intermittent Androgen Deprivation (IAD): IAD is a potential treatment option developed to help counteract both the short-term and long-term side effects associated with continuous LHRH-agonist use. This treatment regimen involves an on-treatment phase and an off-treatment phase. The initial on-treatment phase is defined as either a fixed interval (usually 6-12 months) or time until a predefined serum PSA level is achieved (usually <4 ng/mL). The subsequent off-treatment phase, which consists of frequent monitoring of serum PSA and testosterone levels, is generally continued until a predefined PSA level is attained. Once this PSA level is achieved (generally 10-20 ng/mL), treatment resumes. The proposed benefits of this cyclic regimen include improved quality of life secondary to both a decrease in side effects and the recovery of testosterone levels during the off-treatment phase, and delayed development of androgen-independent disease.24
Most of the clinical data regarding IAD come from phase II trials involving a small heterogeneous patient population. These studies included patients in different stages of disease progression, from localized to metastatic to relapse; they were conducted using an LHRH agonist with or without an antiandrogen; and therapy was directed according to serum PSA levels.25 These studies helped clinicians ascertain the appropriate IAD protocols as well as validate IAD's safety.25 The optimal values for stopping and restarting treatment were established in a study by Goldenberg et al.26 Patients were initially treated until the predefined serum PSA level (<4 ng/mL) was achieved and then restarted when serum PSA increased to a mean value of 10 to 20 ng/mL.26 Patients had a mean survival of 210 weeks. This study concluded that IAD did not have a negative effect on overall survival and that the off-treatment phase was associated with improved quality of life.26
Currently, multiple phase III studies are being conducted to compare IAD with continuous androgen deprivation or CAB. These studies are evaluating quality of life, rates and severity of side effects, and overall survival. One such phase III trial, the South European Uroncological Group (SEUG) study, is comparing IAD plus CAB with continuous CAB and assessing overall survival and quality of life.27 The preliminary data available for the SEUG study are promising; they show no significant difference in overall survival, and the IAD arm had fewer associated side effects.27 The results of the other ongoing trials will help determine IAD's ultimate place in therapy. Until then, the routine use of IAD is not recommended by any guidelines.
Future Therapy: Currently, two therapeutic vaccines are being investigated to determine their utility for the treatment of castration-resistant prostate cancer (CRPC). The theoretical benefit of these agents is that they target some of the tumor-associated antigens linked specifically to prostate cancer.
A recent phase III trial of sipuleucel-T (Provenge) versus placebo assessed time to disease progression and overall survival in metastatic CRPC patients.28 The vaccine was administered at weeks 0, 2, and 4. Although the trial did not find a statistically significant difference in time to progression, there was a statistically significant difference in overall survival: At 36 weeks, overall survival was 34% in the vaccine arm versus 11% in the placebo arm (P = .005).28
The second agent, Prostvac (Vaccinia-PSA-TRICOM and Fowlpox-PSA-TRICOM), is given as a priming dose and followed with monthly booster doses. Prostvac was recently compared with placebo in a phase II study; endpoints were time to progression and overall survival.29 This study, like the phase III trial of sipuleucel-T, found no benefit in terms of delaying time to disease progression, but it did show a statistically significant difference in overall survival: The vaccine arm had an 8.5-month increase in overall survival versus placebo (P = .015).29
Conclusion
Studies exploring ways to help optimize prostate cancer treatment are ongoing. Controversy surrounds when to screen for prostate cancer and whether preventive medicine is beneficial. The use of hormonal therapy is emerging in patients with localized disease despite scarce data. Degarelix has the potential to become first-line therapy since it does not cause the testosterone surge associated with LHRH agonists. Published guidelines have conflicting recommendations regarding CAB use. The potential benefits of IAD therapy are being evaluated.
Castration, whether surgical or medical, is first-line therapy for advanced prostate cancer. Until data from ongoing trials of the above treatments are available, the current recommendation for achieving medical castration is monotherapy with an LHRH agonist. Patients at high risk for experiencing complications from the initial testosterone surge should receive a nonsteroidal antiandrogen at therapy onset. According to the NCCN, the use of CAB may be considered in patients who do not attain adequate testosterone suppression.
REFERENCES
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71-96.
2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Prostate cancer. V.2.2009.
www.nccn.org/professionals/
3. Huhtaniemi I, White R, McArdle CA, Persson BE. Will GnRH antagonists improve prostate cancer treatment? Trends Endocrinol Metab. 2009;20:43-50.
4. Crawford ED. Understanding the epidemiology, natural history, and key pathways involved in prostate cancer. Urology. 2009;73(suppl 5):S4-S10.
5. Andriole GL, Crawford ED, Grubb RL III, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310-1319.
6. Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320-1328.
7. American Urological Association. Prostate-specific antigen best practice statement: 2009 update.
www.auanet.org/content/
8. Gaziano JM, Glynn RJ, Christen WG, et al. Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study II randomized controlled trial. JAMA. 2009;301:52-62.
9. Kramer BS, Hagerty KL, Justman S, et al. Use of 5alpha-reductase inhibitors for prostate cancer chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline. J Urol. 2009;181:1642-1657.
10. Lupron Depot (leuprolide acetate) package insert. Lake Forest, IL: TAP Pharmaceutical Products Inc; 2004.
11. Zoladex (goserelin acetate implant) package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; November 2008.
12. Casodex (bicalutamide) package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; December 2008.
13. Degarelix package insert. Parsippany, NJ: Ferring Pharmaceuticals Inc; December 2008.
14. Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med. 1998;339:1036-1042.
15. Ansari MS, Gupta NP, Hemal AK, et al. Combined androgen blockade in the management of advanced prostate cancer: a sensible or ostensible approach. Int J Urol. 2004;11:1092-1096.
16. Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA. 2005;294:238-244.
17. American Urological Association. Prostate cancer. Guideline for the management of clinically localized prostate cancer: 2007 update.
www.auanet.org/content/
18. Lu-Yao GL, Albertsen PC, Moore DF, et al. Survival following primary androgen deprivation therapy among men with localized prostate cancer. JAMA. 2008;300:173-181.
19. Boustead G, Edwards SJ. Systematic review of early vs deferred hormonal treatment of locally advanced prostate cancer: a meta-analysis of randomized controlled trials. BJU Int. 2007;99:1383-1389.
20. Ryan CW, Huo D, Bylow K, et al. Suppression of bone density loss and bone turnover in patients with hormone-sensitive prostate cancer and receiving zoledronic acid. BJU Int. 2007;100:70-75.
21. Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008;102:1531-1538.
22. Loblaw DA, Mendelson DS, Talcott JA, et al. American Society of Clinical Oncology recommendations for the initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer. J Clin Oncol. 2004;22:2927-2941.
23. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25:1596-1605.
24. Tunn U. The current status of intermittent androgen deprivation (IAD) therapy for prostate cancer: putting IAD under the spotlight. BJU Int. 2007;99(S1):19-22.
25. Boccon-Gibod L, Hammerer P, Madersbacher S, et al. The role of intermittent androgen deprivation in prostate cancer. BJU Int. 2007;100:738-743.
26. Goldenberg SL, Bruchovsky N, Gleave ME, et al. Intermittent androgen suppression in the treatment of prostate cancer: a preliminary report. Urology. 1995;45:839-844.
27. Da Silva FC, Bono A, Whelan P, et al. Phase III study of MAB versus continuous MAB--an international cooperative study--quality of life. Eur Urol. 2006;5:289. Abstract 1066.
28. Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006;24:3089-3094.
29. Madan RA, Arlen PM, Mohebtash M, et al. Prostvac-VF: a vector-based vaccine targeting PSA in prostate cancer. Expert Opin Investig Drugs. 2009;18:1001-1011.
To comment on this article, contact rdavidson@jobson.com.
