Androgen Deprivation Therapy: A Cornerstone in the Treatment of Advanced Prostate Cancer

LHRH AGONISTS: CONTEMPORARY ISSUES Androgen Deprivation Therapy: A Cornerstone in the Treatment of Advanced Prostate Cancer Michael K. Brawer, MD Northwest Prostate Institute, Northwest Hospital, Seattle, WA Decreased incidence of prostate cancer, improved therapies, and early detection have all have played some role in the decrease in prostate cancer mortality. The author discusses the development of improved methods of androgen deprivation therapy and demonstrates its significance in improved management of prostatic carcinoma. [Rev Urol. 2004;6(suppl 8):S3-S9] © 2004 MedReviews, LLC Key words: Hormone therapy •Androgen deprivation therapy • Mortality rates ver the last 2 decades, there have been significant advances in the management of men with prostatic carcinoma. Concomitant with these advances is a small but real reduction in prostate cancer mortality in the United States. There are 3 factors associated with decreasing the mortality of any disease: decreasing the incidence, improving therapy, and providing a mechanism for early detection. To decrease the incidence of prostate cancer, a number of chemopreven- O VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY S3 Androgen Deprivation Therapy continued tative regimens have been applied. Most recently the Prostate Cancer Prevention Trial demonstrated a significant reduction in the incidence of prostate cancer among men treated with finasteride versus placebo for 7 years.1 Significant controversies surround this study, particularly that the men on finasteride had more aggressive cancer detected. However, the trial undoubtedly will be the first of many focused on the incidence of prostatic carcinoma. The biggest advance in prostate cancer has been early detection. Prostate-specific antigen (PSA) testing has revolutionized the diagnosis Despite the significant stage migration afforded by earlier detection and improvements in local therapy, the failure rate of our most widely applied approaches (radical prostatectomy and radiation therapy) is prohibitively high. Even in one of the most favorable cohorts of patients treated at the Johns Hopkins University Medical Center, an overall 15% biochemical failure rate has been reported,2 and similar failure rates have been reported in numerous other surgical and radiation series. Despite seemingly effective therapy and clinically localized disease, why does conventional treatment fail? Concomitant with advances in the management of men with prostatic carcinoma is a small but real reduction in prostate cancer mortality in the United States. of prostate cancer and has become the mainstay of early detection and screening programs. Credit must also be given to the advent of transrectal ultrasound and spring-loaded biopsy devices, which provide easier sampling of prostatic tissue. There is no question that significant strides have been made in lessening the morbidity of our most common therapeutic procedures. Anatomic radical prostatectomy (nerve sparing) has resulted in decreasing incidence of erectile dysfunction and urinary incontinence following surgery. Improvements in radiation therapy, namely, advances in brachytherapy and more directed external beam radiation therapy, have lessened complications. Additionally there has been more widespread utilization of androgen deprivation therapy in men with prostate cancer following the development of luteinizing hormone-releasing hormone (LHRH) agonist, which has been associated with improvements in overall therapy. S4 VOL. 6 SUPPL. 8 2004 First, the therapy may be unable to sterilize the tumor within the field. Although this is not the case in radical prostatectomy, this may be a factor in radiation or other nonsurgical approaches. Second, the therapy may be inadequate—the tumor may extend beyond the margins of resection in radical prostatectomy or in the radiation port. Third and most importantly, there is the likelihood of occult systemic disease. Prostate cancer cells are found in the systemic circulation and in the bone marrow in virtually all patients. Clones that can establish metastatic deposits can be missed by imaging modalities. And finally, in therapies where prostatic epithelium is left behind there may be actual recurrence or development of new malignancy. In light of these potential limitations of conventional treatment, what adjuvant therapies can applied? Options include applying more aggressive therapy, such as dose escalation in radiation, which has become more REVIEWS IN UROLOGY and more common. Different therapeutic approaches can be combined: for example, radiation plus surgery. The field of therapy can be expanded with wider resection in radical prostatectomy or extended field in radiation therapy. The target malignancy can be shrunk, which has been demonstrated effectively utilizing androgen deprivation therapy, but whether this results in down staging remains controversial. Finally, systemic therapy can be applied to achieve shrinkage of the known target malignancy and potentially eradicate occult metastatic disease. It is safe to assume that decreased incidence, improved therapies, and earlier detection have all played some role in the decrease in prostate cancer mortality. In this article, the development of improved methods of androgen deprivation therapy (ADT) will be examined and its significance in improved management of prostatic carcinoma will be demonstrated. The Role of Hormones in Prostate Cancer There are many similarities between breast and prostate cancer, none greater than the commonality of hormonal control. In women with breast cancer, adjuvant therapy with the anti-estrogen tamoxifen demonstrated a reduced risk of recurrence of breast cancer by 47% in a meta-analysis. Moreover, mortality decreased by one fourth.3 The success of hormonal therapy in breast cancer has resulted in numerous investigations of androgen reduction therapy in men with prostate cancer. Circulating androgens are a prerequisite for the growth of the normal prostate and are clearly implicated in the development and expansion of epithelial cell clones that can undergo malignant transformation. Whereas the specific action of androgens in the process of carcinogenesis remains an Androgen Deprivation Therapy 100 Placebo DES 5.0 mg DES 0.2 mg DES 1.0 mg 90 80 % Surviving 70 60 50 40 30 20 10 0 0 2 1 3 4 5 6 7 Years Figure 1. Actuarial survival curves of all causes of death for patients in stages C and D2 in a Veterans Administration Cooperative Urological Reasearch Group study. Adapted with permission from Byar and Corle.24 DES, diethylstilbestrol. Arrow indicates survival advantage at the 1.0 mg level. men with prostate cancer. Several of these studies are discussed below. Radiation therapists have conducted a number of outstanding studies utilizing androgen deprivation therapy in conjunction with conventional radiation therapy and these will be described by Dr. Roach in this issue. The Veterans Administration Cooperative Study Group carried out a number of investigations on the use of adjuvant hormonal therapy in men with prostatic carcinoma. Byar and dation for the interest in using androgen deprivation in conjunction with other therapies in men with high-risk prostatic carcinoma. Studies Involving Androgen Deprivation Therapy as a Treatment for Prostate Cancer A number of studies demonstrate more favorable outcomes when androgen deprivation is added as either an adjuvant or neoadjuvant therapy to conventional treatment in Major Complications 60 P < .025 P < .05 50 Frequency 40 30 P = NS Immediate Deferred P < .025 20 10 Ex M tra et Sk as el ta et se al s bs Ure tr te uc r tio n O Co m Cor pr d es sio n 0 Pa Fr tho ac lo tu gi re c issue of considerable investigation, it is believed that androgens promote cellular growth and division and prostate carcinogenesis. Testosterone is a specific stimulus to the prostate. It is recognized that the conversion of testosterone to dihydrotestosterone (DHT) results in significant stimulus amplification leading to greater adherence to the androgen receptor.4 Conversion of testosterone to DHT occurs by the enzyme 5-alpha-reductase.5 The requirement of DHT for prostatic development has been well established by a natural history experiment of pseudo-hermaphrodite men who have intrinsic 5-alphareductase deficiency. The binding of DHT to the androgen receptor results in increased transcription of androgen-regulated genes.6,7 Prostate carcinogenesis is undoubtedly exceedingly complex and most authorities believe it to be a multistep process.8 A relatively small population of transformed cells may allow establishment of clones inheriting the genetic change required for the development of the malignant phenotype. Cellular proliferation stimulated by androgens allows for increased genetic instability.9 This may allow cell clones beyond the abilities of conventional therapy to eradicate to undergo further malignant transformation and achieve a more aggressive malignant potential. Eventually this may lead to the ultimate progression of disease despite local therapy. A number of animal models demonstrate that androgens are required to establish prostate cancer. Moreover, this occurs in a dosedependent fashion.10 In humans, administration of testosterone in men with established malignancy has resulted in clear clinical progression both when given therapeutically11 and with the surge-and-flare associated with LHRH agonist administration.12–23 These observations serve as the foun- Figure 2. Immediate versus deferred treatment for advanced prostate cancer in the Medical Research Council trial. Data from Kirk.25 NS, not significant. VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY S5 Androgen Deprivation Therapy continued Causes of Death P < .01 400 350 P < .001 Frequency 300 250 Immediate Deferred 200 150 100 50 0 All Deaths Death from Prostate Cancer Figure 3. Treatment for advanced prostate cancer in the Medical Research Council trial. Data from Kirk.25 Corle re-examined data from one of these studies and demonstrated a survival advantage for men with advanced local prostatic carcinoma (T3) or metastatic (M+) disease. Men receiving 1 mg per day of diethylstilbestrol demonstrated a survival advantage as compared with those on placebo, or on the 0.2-mg dose (inadequate for achieving castration), or the 5-mg dose, which was associated with increased cardiovascular mortality (Figure 1).24 A Medical Resource Council (MRC) study25 involved 987 men with clinical stage T3 or M+ prostate cancer, making it a similar cohort to that reported in the VA study. Men were randomized to receive immediate androgen deprivation therapy by either surgical castration or an LHRH agonist versus watchful waiting. Although this study may be faulted on a number of issues, most importantly that some of the men on watchful waiting never received androgen deprivation before death, the study clearly demonstrates, by virtually all parameters, more favorable outcomes than those receiving early androgen deprivation therapy. Figure 100 Early Hormones % Survival 75 50 Late Hormones 25 0 0 1 2 3 4 5 6 7 8 9 10 Years Since Randomization Figure 4. Survival benefit of earlier hormone therapy in nonmetastatic disease. Adapted with permission from Kirk et al.25 S6 VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY 2 demonstrates that with respect to major complications, both statistically and clinically significant outcomes favored early androgen deprivation. When examining causes of death the study demonstrated a reduction in both all-cause mortality and prostate cancer deaths related to treatment with early androgen deprivation therapy (Figure 3). Overall survival benefit in a Kaplan–Meier survival curve is depicted in Figure 4. This study confirms the initial observation noted in the VA study that the survival benefit accrues to those who receive early hormonal therapy in advanced prostate cancer. Moreover, studies with adjuvant and neoadjuvant hormone therapy in men treated with external beam radiation therapy have further supported the contention that men with advanced prostate cancer benefit from androgen deprivation.25 In 1999, the Eastern Cooperative Oncology Group reported results of a study comparing immediate hormonal therapy to observation in men undergoing radical prostatectomy where pelvic lymph node metastases were detected.26 In this investigation, 98 men were randomized to receive hormonal therapy with goserelin or orchidectomy versus observation until evidence of disease progression. This study demonstrated a statistically significant all-cause survival advantage and prostate cancer–specific survival advantage. Favoring early hormonal therapy at a median followup of 10 years, 72.4% of patients were alive who received the androgen deprivation compared with 49% of those on observation. Cause-specific survival was 87.2% in patients receiving early hormonal therapy versus 56.9% in the comparison group (Figure 5). Neoadjuvant hormone therapy in conjunction with radical prostatectomy (although initially believed to be encouraging) has fallen into disfavor. Despite gland and tumor volume Androgen Deprivation Therapy Immediate Therapy 1.0 Prostate Cancer–Specific Survival reduction and improved clinical and pathologic stage, as well as decreased margin positivity rates,27 biochemical failure has not improved.28 The discrepancy between the radical prostatectomy experience and radiation therapy remains controversial. It may be that androgen deprivation acts in a more synergistic fashion in association with radiation therapy. Alternatively, longer follow-up may be needed in the radical prostatectomy cohort in part because there may be more favorable pathologic considerations with respect to malignant potential in men undergoing surgery. Studies are ongoing with longer androgen deprivation prior to radical prostatectomy.29,30 It was the success of the antiandrogen program with tamoxifen in conjunction with the improved outcomes of men receiving hormonal therapy as an adjunct to radical prostatectomy that led to the bicalutamide early prostate cancer program, the largest prostate cancer trial ever conducted. Patients with prostate cancer undergoing a variety of therapeutic approaches were randomized to receive 150 mg bicalutamide qid versus placebo. The 3 major treatment groups included men undergoing radical prostatectomy, radiation therapy, or watchful waiting. Patients were enrolled with either localized or locally advanced disease. The studies were conducted throughout the world: 8113 men were randomized to a 3-year treatment regimen in the North American study and to a 5-year treatment regimen in the 2 others. Fiftyfive percent of patients underwent radical prostatectomy, 17% radiation therapy, and 28% watchful waiting. Findings are shown in Figure 6. The overall findings demonstrated that in addition to standard care, bicalutamide resulted in a significant reduction in the risk of objective progression (which was defined as develop- Observation 0.8 0.6 0.4 0.2 P = .001 0.0 0 20 40 60 100 80 120 Months Figure 5. Hormonal therapy versus observation after surgery for node-positive prostate cancer. Adapted with permission from Messing et al.26 ment of a positive bone scan or other imaging modalities, or death) of 9% versus 13.8% (P < .0001).31,32 Patients who received bicalutamide with a worse prognosis had more significant reduction in objective progression. There was a 59% reduction relative to placebo in the PSA doubling time in patients receiving bicalutamide. PSA dou- bling time has recently been demonstrated33 as an important predictor of prostate cancer death. No difference in all-cause or prostate cancer–related death was observed at the time of the first report. Recently there has been concern over increased nonprostate cancer–related death in men receiving bicalutamide, which has rendered this therapeutic approach Overall Analysis (N = 8113, E = 922) Radical prostatectomy (n = 4454, E = 285) Radiotherapy (n = 1370, E = 178) Watchful waiting (n = 2285, E = 458) Localized disease (n = 5429, E = 480) Locally advanced disease (n = 2682, E = 442) No (n = 3157, E = 501) NX (n = 4806, E = 378) N+ (n = 150, E = 43) Gleason Score 2-4 (n = 1792, E = 208) X Gleason Score 5-6 (n = 3598, E = 376) X Gleason Score 7-10 (n = 2648, E = 327) X Pretherapy PSA ≤ 4 ng/mL (n = 918, E = 72) Pretherapy PSA > 4 to ≤ 10 ng/mL (n = 3230, E = 226) Pretherapy PSA > 10 ng/mL (n = 3719, E = 592) 0.125 0.25 0.5 1.0 2.0 4.0 HR plus 95% CI Figure 6. The overall findings of the Bicalutamide Early Prostate Cancer Program demonstrate that in addition to standard care, bicalutamide resulted in a significant reduction in the risk of objective progression. PSA, prostatespecific antigen; HR, hazard ratio; E, events; CI, confidence interval. Reproduced with permission from See.32 VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY S7 Androgen Deprivation Therapy continued unfavorable by most clinicians. Further follow-up and clarification of this is required. The bicalutamide early prostate cancer program has been the subject of a recent Reviews in Urology supplement.34 In the considerably more favorable vant and adjuvant setting, early androgen deprivation in men with more aggressive prostate cancer may indeed expand the cure rate of conventional therapy. Additional studies in a variety of settings and long-term follow-up are required to definitively Recently there has been concern over increased nonprostate cancer–related death in men receiving bicalutamide, which has rendered this therapeutic approach unfavorable by most clinicians. 7. 8. 9. 10. 11. cohort of men who had radical prostatectomy in this trial, bicalutamide reduced the risk of objective progression 37% (5.1% progression rate) versus placebo (7.7% progression rate).35 Overall, the study demonstrated that those patients at higher risk for progression due to Gleason score, pretherapy PSA level, and postprostatectomy PSA level received the greatest benefit from bicalutamide.32 assess the adequacy of these approaches and potential complications. However, androgen deprivation should be considered as part of the therapeutic approach in men with high-risk prostate cancer. References 1. 2. Future Directions It is disheartening to note that despite significant improvements in early detection, the 2 most widespread approaches to therapy with curative intent, radical prostatectomy and radiation therapy, have significant rates of failure. Therapeutic firepower needs to be increased without increasing morbidity. Androgen deprivation therapy has been demonstrated to be effective in this regard in a variety of clinical situations. Both in a neoadju- 3. 4. 5. 6. Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. N Engl J Med. 2004;350:2239–2246. Han M, Partin AW, Pound CR, et al. Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am. 2001;28:555–565. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists' Collaborative Group. Lancet 1992;339:1–14. Mettlin C. Changes in patterns of prostate cancer care in the United States: results of American College of Surgeons Commission on Cancer Studies, 1974-1993. Prostate 1997;32:221–226. American Cancer Society. Prostate Cancer Resource Center. http://www.cancer.org/cancerinfo. Accessed August 10, 2001. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 12. 13. 14. 15. 16. 17. 18. 19. 1999;281:1591–1597. Lai S, Lai H, Krongrad A, Roos BA. Overall and disease-specific survival after radical prostatectomy: geographic uniformity. Urology 2001;57: 504–509. Trapasso JG, deKernion JB, Smith RB, Dorey F. The incidence and significance of detectable levels of serum prostate-specific antigen after radical prostatectomy. J Urol. 1994;152:1821–1825. Amling CL, Blute ML, Bergstralh EJ, et al. Longterm hazard of progression after radical prostatectomy for clinically localized prostate cancer: continued risk of biochemical failure after 5 years. J Urol. 2000;164:101–105. Van Weerden WM, van Steenbrugge GJ, van Kreuningen A, et al. Assessment of the critical level of androgen for growth response of transplantable human prostatic carcinoma (PC-82) in nude mice. J Urol. 1991;145:631–634. Fowler JE Jr, Whitmore WF Jr. The response of metastatic adenocarcinoma of the prostate to exogenous testosterone. J Urol. 1981;126: 372–375. 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. Thompson IM, Zeidman EJ, Rodriguez FR. Sudden death due to disease flare with luteinizing hormone-releasing hormone agonist therapy for carcinoma of the prostate. J Urol. 1990; 144:1479–1480. Smith JA Jr, Glode LM, Wettlaufer JN, et al. Clinical effects of gonadotropin-releasing hormone analogue in metastatic carcinoma of the prostate. Urology 1985;25:106–114. Kreis W, Ahmann FR, Jordan VC, et al. Oestrogen pre-treatment abolishes lutenizing hormone-releasing hormone testosterone stimulation. Br J Urol. 1988;62:352–354. Waxman J, Man A, Hendry WF, et al. Importance of early tumour exacerbation in patients treated with long acting analogues of gonadotrophin releasing hormone for advanced prostatic cancer. Br Med J (Clin Res Ed). 1985;291:1387–1388. Kuhn JM, Billebaud T, Navratil H, et al. Prevention of the transient adverse effects of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide). N Engl J Med. 1989;321:413–418. Waxman J. A review of the Hammersmith Hospital, St. Bartholomew's Hospital, and Institute of Urology studies of buserelin in advanced prostatic cancer. Am J Clin Oncol. 1988;11(suppl 1):S16–S18. Trachtenberg J. The treatment of metastatic prostatic cancer with a potent luteinizing hormone Main Points • There are three factors associated with decreasing the mortality of any disease: decreasing the incidence, improving therapy, and providing a mechanism for early detection. • The success of hormonal therapy in breast cancer has resulted in numerous investigations of androgen reduction therapy in men with prostate cancer. • A number of studies demonstrate more favorable outcomes when androgen deprivation is added as either an adjuvant or neoadjuvant therapy to conventional treatment in men with prostate cancer. • Both in a neoadjuvant and adjuvant setting, early androgen deprivation in men with more aggressive prostate cancer may expand the cure rate of conventional therapy. S8 VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY Androgen Deprivation Therapy 20. 21. 22. 23. 24. 25. releasing hormone analogue. J Urol. 1983;129: 1149–1152. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. The Leuprolide Study Group. N Engl J Med. 1984;311:1281–1286. Klign JG, de Voogt HJ, Schroder FH, de Jong FH. Combined treatment with buserelin and cyproterone acetate in metastatic prostatic carcinoma. Lancet 1985;2:493. Peeling WB. Phase III studies to compare goserelin (Zoladex) with orchiectomy and with diethylstilbestrol in treatment of prostatic carcinoma. Urology 1989;33(suppl 5):45–52. Kahan A, Delrieu F, Amor B, et al. Disease flare induced by D-Trp6-LHRH analogue in patients with metastatic prostatic cancer. Lancet 1984; 1:971–972. Byar DP, Corle DK. Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group studies. NCI Monogr. 1988:7;165–170. Kirk D. MRC study: when to commence treatment in advanced prostate cancer. Prostate Cancer Prostatic Dis. 1997;1:11–15. 26. 27. 28. 29. 30. Messing EM, Manola J, Sarosdy M, et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with nodepositive prostate cancer. N Engl J Med. 1999; 341:1781–1788. Bono AV, Pagano F, Montironi R, et al. Effect of complete androgen blockade on pathologic stage and resection margin status of prostate cancer: progress pathology report of the Italian PROSIT study. Urology 2001;57:117–121. Soloway MS, Pareek K, Sharifi R, et al. Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5year results. J Urol. 2002;167:112–116. Gleave ME, Goldenberg SL, Chin JL, et al. Randomized comparative study of 3 versus 8month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and pathological effects. J Urol. 2001;166:500–506; discussion 506–507. Crook J, Ludgate C, Malone S, et al. Multicenter Canadian phase III randomized trial of 3 months vs. 8 months neoadjuvant androgen deprivation 31. 32. 33. 34. 35. radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys. 2004; 60:15–23. See WA, Wirth MP, McLeod DG, et al. Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program. J Urol. 2002;168:429–435. See WA. Bicalatamide adjuvant to radical prostatectomy. Rev Urol. 2004;6(suppl 2):S20S28. D'Amico AV, Chen MH, Roehl KA, Catalona WJ. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med. 2004;351:125–135. Brawer MK, ed. Update on the Treatment of Prostate Cancer: The Role of Adjuvant Hormonal Therapy. Rev Urol. 2004;6(suppl 2):S1-S32. Klimberg I, See WA, Wirth MP, et al. New analysis shows that bicalutamide 150 mg as adjuvant to radical prostatectomy significantly increases progression-free survival in early prostate cancer [abstract]. J Urol. 2003;169(suppl 4):180. VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY S9