A Critical Review of Maximal Androgen Blockade for Advanced Prostate Cancer

LHRH AGONISTS: CONTEMPORARY ISSUES A Critical Review of Maximal Androgen Blockade for Advanced Prostate Cancer Gerald W. Chodak, MD Midwest Prostate and Urology Health Center, University of Chicago, Weiss Memorial Hospital, Chicago, IL For over 60 years, the primary treatment for metastatic prostate cancer has been androgen ablation. Medical or surgical castration eliminates most, but not all androgen production, with a small contribution still coming from the adrenal gland. When castration fails, secondary adrenalectomy can provide some palliative benefit. However, the development of oral antiandrogens has offered an opportunity to simultaneously interfere with androgen produced in the testes and adrenal gland. Combined androgen blockade (CAB) has been investigated extensively with conflicting results. Based on a critical review of these studies, CAB still appears to offer the longest duration of survival and should continue to be offered as an option to men with metastatic disease. [Rev Urol. 2004;6(suppl 8):S18-S23] © 2004 MedReviews, LLC Key words: Prostate cancer • Combined androgen blockade • Maximal androgen blockade • Antiandrogens • Castration rostate cancer is currently the most common solid tumor and the second most common cause of death from cancer in the United States; approximately 200,000 new cases may be diagnosed in 2004. Although the death rate has gradually declined since 1993, approximately 30,000 men will die from this disease in 2004. Until the development of prostate-specific antigen (PSA) screening tests, the majority of men were diagnosed with advanced and often metastatic disease. P S18 VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY MAB for Advanced Prostate Cancer The disease is curable either by surgery or radiation if diagnosed in a localized stage. However, the disease remains essentially incurable if it has spread to other parts of the body. Once metastases occur, the most successful treatment has been androgen ablation. This treatment was first reported in 1941 by Huggins and Hodges.1 Despite many medical advances since its discovery, andro- which prevent the production of testosterone by the testes. LHRH agonists achieve the same level of testosterone reduction as orchiectomy and estrogen and are now the most common form of androgen ablation. Although medical and surgical castration suppresses testicular testosterone to a similar degree, neither affects adrenal androgens. Laboratory studies suggest that even very low Interfering with the production of androgens in the adrenal gland has the potential to interfere with the growth of prostate cancer. gen ablation remains the primary therapy for this stage of disease. The physiologic mechanism for this therapy has been well defined.2 A small peptide called luteinizing hormonereleasing hormone (LHRH) is produced in the hypothalamus. When released, it stimulates the production of luteinizing hormone (LH) in the pituitary gland. LH is then released into the circulation and reaches the testes where it stimulates the leydig cells to produce testosterone. Approximately 95% of serum testosterone is derived from the testes with the remainder coming from androgens produced in the adrenal gland. Once entering the serum, testosterone binds to sex hormone binding globulin, which enables the testosterone to enter the prostate cell cytoplasm. There it is converted to dihydrotestosterone (DHT) by 5
-reductase. The DHT enters the nucleus, binds to the androgen receptor, and stimulates cell growth. Interfering with any step in this pathway has the potential to interfere with the growth of prostate cancer. Androgen ablation was traditionally accomplished by performing a bilateral orchiectomy or administering estrogen orally.1 However, the discovery of the structure of LHRH led to the development of LHRH agonists, levels of androgens may stimulate prostate cancer cell growth.3 Huggins hypothesized that prostate cancer patients whose disease progressed after castration might get a secondary benefit by interfering with adrenal androgens.4 This led him to perform surgical adrenalectomy, which achieved some palliative benefit in such men. Thus, the concept of combined or maximal androgen blockade (MAB) evolved. The development of a new class of compounds called antiandrogens provided a nonsurgical way to inter- cal way to achieve maximal androgen ablation. Beginning in the 1980s, many prospective, randomized studies were performed throughout the world to compare simultaneous maximal androgen ablation to castration alone. These studies used either bilateral orchiectomy or an LHRH agonist for castration and either flutamide, nilutamide, or cyproterone acetate as the antiandrogen. Cyproterone acetate is a steroidal antiandrogen whereas the other 2 drugs are nonsteroidal antiandrogens. From 1980 to 1991, approximately 36 prospective, randomized studies were performed, 27 of them being reasonably well designed with at least 1 year of therapy. Of these, only 3 showed a statistically significant improvement in overall survival.8-11 The first study was sponsored by the National Cancer Institute (NCI) in the United States and compared daily leuprolide (1 mg/day) and flutamide (250 mg 3 times a day) to leuprolide and placebo.8 At the time of enrollment, patients were classified into groups according to their performance and extent of disease. All participants had objective evidence of minimal M1 After 8.5 years of follow-up, the MAB group showed a significant improvement in median time to progression compared with the control group, as well as an improvement in overall survival. fere with adrenal androgens.5 These drugs were competitive inhibitors of the binding between DHT and the androgen receptor in the nucleus. Human studies demonstrated a clinical benefit from antiandrogen monotherapy in men with advanced prostate cancer.6 Unfortunately, for men with metastatic disease, antiandrogens alone were slightly inferior to castration.7 The availability of oral antiandrogens, however, presented a nonsurgi- (distant metastasis) disease, defined as the absence of metastases in the skull, ribs, long bones, and soft tissues excluding lymph nodes. An interesting feature of this study was that it included a crossover design. Once patients met the criteria for progression based on changes in the bone scan, their treatment was unblinded and those receiving the placebo could then receive flutamide whereas those initially receiving the flutamide were treated according to VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY S19 MAB for Advanced Prostate Cancer continued Androgen suppression only Androgen suppression + nilutamide/flutamide 100 Proportion Alive (%) 80 6500 men in 20 trials of nilutamide or flutamide 60 40 27.6% 20 Treatment better by 2.9% (SE 1-3) Logrank 2P = .005 24.7% 0 0 1 2 3 4 5 Time Since Randomization (years) Figure 1. 5-year survival in 20 randomized trials using nonsteroidal agents. The lower confidence limit for the observed 2.9% difference in survival barely exceeds zero, giving it only weak statistical significance. Reproduced from Prostate Cancer Trialists’ Collaborative Group12 with permission. the doctor’s preference. Essentially this study compared early to delayed MAB. The study enrolled over 600 patients and found that the combination of flutamide and leuprolide resulted in a significantly longer progression-free survival (P = .039) and overall median survival (35.6 months vs 28.3 months, P = .035) when compared with the control group.8 The benefit was more pronounced for men with minimal disease. The second study was designed to compare bilateral orchiectomy and placebo to bilateral orchiectomy and nilutamide in men with M1 disease. The antiandrogen was administered at 300 mg/day for 1 month followed by 150 mg/day.9 After 8.5 years of follow-up, the MAB group showed a significant improvement in median time to progression compared with the con- S20 VOL. 6 SUPPL. 8 2004 trol group (21.2 months vs 14.7 months, respectively, P = .002), as well as an improvement in overall survival (37 months vs 29.8 months, P = .013).10 The last study to show a significant benefit of MAB was performed by the European Organization for Research trial, this translated into a 7-month increase in overall survival. When the results were compared for men with positive prognostic factors, mortality was reduced by 39%. Despite the findings from these 3 studies, the lack of benefit in any of the other 24 studies led to much debate about the overall benefit of MAB in men with metastatic disease. In an effort to eliminate possible differences in patient cohorts and in order to base any conclusions on a much larger number of patients, a comprehensive meta-analysis was initiated of all the published and unpublished randomized studies of MAB that began before 1991. The total number of men enrolled in these studies was over 8000, in whom almost 90% had metastases at the time of treatment. In this very impressive evaluation, all the original data were obtained from the respective investigators (whether the study was published or not), and most researchers also provided updated information. When the re-analysis was completed, MAB resulted in an absolute increase in survival of about 2% (70.4% vs 72.4% mortality at 5 years for the control and MAB groups, respectively).12 Further analysis revealed, however, that the outcome for MAB using the steroidal antiandrogen cyproterone acetate was sig- Despite the findings from these 3 studies, the lack of benefit in any of the other 24 studies led to much debate about the overall benefit of MAB in men with metastatic disease. and Treatment of Cancer (EORTC). The EORTC 30853 trial enrolled over 450 men with metastases and compared bilateral orchiectomy to monthly depot goserelin acetate (3.6 mg) combined with flutamide (250 mg 3 times a day).11 The study showed a 23% reduction in mortality. Similar to the NCI REVIEWS IN UROLOGY nificantly inferior compared to the outcome using the nonsteroidal agents. In fact, when using the combination of castration and cyproterone acetate, the survival was significantly inferior to castration alone.12 As shown in Figure 1, when the analysis combined all the studies MAB for Advanced Prostate Cancer 1.0 0.9 0.8 Proportion Surviving using nonsteroidal agents, there was a small but significant improvement in the 5-year survival rate (27.6% vs 24.7%, P = .005).12 Based on this report, many experts in the United States considered that a survival benefit of only 3% from MAB was overshadowed by its cost and side effects. Absent from the criticism of MAB was the acknowledgment that a similar 3% survival benefit was achieved with adjuvant tamoxifen for breast cancer, which has now been accepted as standard therapy. Also absent was recognition of the flaws in the meta-analysis that significantly compromised its findings. 0.7 0.6 0.5 0.4 0.3 0.1 0.0 Critique of the Meta-Analysis There are 5 potential problems with the meta-analysis that raise serious questions about whether its findings and conclusions are valid. The most important of these is the fundamental premise that all MAB regimens yield similar results. If this were true, then combining the results from the various studies would be reasonable. However, a subset analysis revealed that combining the studies comparing orchiectomy and nilutamide to orchiectomy and placebo had a relative survival risk of 1.68.12 In contrast, the same comparison using flutamide in place of nilutamide yielded a relative risk of only 1.22.12 Also absent were the results from a 4-arm, double-blinded comparison of MAB regimens: leuprolide + flutamide, leuprolide + bicalutamide, goserelin + flutamide, and goserelin + bicalutamide. In this study, the 2 arms using flutamide resulted in an inferior survival curve compared to the 2 arms that used bicalutamide (P = .047).13 In addition, the combination of flutamide and leuprolide gave significantly inferior results (P = .008), as can be seen in Figure 2. Together, these findings demonstrate that the meta-analysis is significantly flawed because it com- leuprolide + bicalutamide goserelin + bicalutamide goserelin + flutamide leuprolide + flutamide 0.2 0 365 730 P = .26 P = .99 P = .047 1095 1460 P = .008 1825 Time to Death (days) Figure 2. Probability of survival for 4 MAB regimens. MAB, maximal androgen blockade. Reproduced from Sarosdy13 with permission. bined the results from studies with dissimilar treatments. No acknowledgment of this potential problem was made in the publication. A second problem is that sample size from the individual trials was not addressed. Many of the trials enrolled too few patients to demonstrate a small but statistically significant difference. Combining several underpowered studies into 1 analysis does not eliminate the possibility that properly powered trials would have shown a benefit. Three of the 5 largest studies demonstrated a statistically significant improvement in survival.8-11 The largest study compared orchiectomy and flutamide to orchiectomy and placebo.14 Although there was a 10% difference in survival, the study had been designed to show a 24% difference.14 This problem could also explain the lack of greater differences between MAB and androgen suppression alone. Another problem relates to the antiandrogen withdrawal phenomenon that was only discovered years after the trials were being completed. Kelly and Scher15 reported that approximately 50% of men with rising PSA levels on an antiandrogen would have at least a 50% decline in the PSA levels within 1 to 2 months of discontinuing the antiandrogen. PSA values were not available when the MAB trials were designed. One endpoint was objective evidence of disease progression on bone scan or computed tomography. Thus patients were actually maintained on the antiandrogen much longer than is now known to be appropriate. In effect, the prolonged use of an antiandrogen may have accelerated disease progression. Had patients stopped the antiandrogen sooner, a greater survival difference could have been detected. A fourth problem is that the metaanalysis failed to characterize the patients according to their risk of disease progression. It compared the results for men with M0 (no distant metastasis) versus M1 disease. However, 2 of the 3 positive studies VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY S21 MAB for Advanced Prostate Cancer continued 1.0 Proportion Surviving suggested that even greater differences in survival were found for M1 patients with favorable outcomes.8,11 As most of the studies were conducted in countries where men would likely be diagnosed with advanced metastatic disease, they would be less likely to find a significant improvement in survival. Lastly, the issue of duration of MAB was never addressed. Sarosdy and colleagues16 performed an analysis of the duration of MAB and its impact on survival based on the 4-arm trial described earlier. They found a highly significant difference in survival for men on MAB for longer than 120 days compared with those on MAB for a shorter duration (Figure 3). In addition, flutamide can cause significant diarrhea and result in early withdrawal. In the largest study using flutamide, 5% discontinued because of side effects,14 which may have contributed to a smaller improvement in survival than that observed in the NCI 0036 trial8 in which no patient discontinued the drug because of side Length of Therapy < 120 Days > 120 Days 0.8 0.6 P = .0001 0.4 0.2 0.0 0 365 730 1095 1460 1825 2190 Day Figure 3. Survival by prolonged versus short-term CAB therapy. CAB, combined androgen blockade. Reproduced from Sarosdy16 with permission. effects. No assessment was made of the impact of early withdrawal in the meta-analysis. These 5 problems provide strong evidence that the findings and conclusions of the meta-analysis may be invalid. An additional reason to question the meta-analysis is that it combined both published and unpub- lished studies without showing similar outcomes for similar treatments. Klotz17 performed such an analysis and found that the results were not the same. Combining very different studies into 1 meta-analysis is not likely to yield a valid conclusion. The studies demonstrated, however, that the longest survival achieved in M1 Main Points • Prostate cancer is currently the most common solid tumor and the second most common cause of death from cancer in the United States. • Despite much medical advancement since its discovery, androgen ablation still remains the primary therapy for metastatic prostate cancer. • A new class of compounds called antiandrogens was developed as a nonsurgical way to interfere with adrenal androgens. These drugs were competitive inhibitors of the binding between dihydrotestosterone (DHT) and the androgen receptor in the nucleus. • From 1980 to 1991, approximately 36 prospective, randomized studies were performed comparing maximal androgen ablation to castration alone. Of these, 3 showed a statistically significant improvement in overall survival. • Because only 3 of the many studies performed between 1980 and 1991 showed maximal androgen blockade (MAB) to be beneficial in men with metastatic disease, a comprehensive meta-analysis was initiated of all the published and unpublished randomized studies of MAB that began before 1991. • There are 5 potential problems with the meta-analysis that raise serious questions about its validity: 1) it combined the results from studies with dissimilar treatments, 2) the sample size from the individual trials was not addressed, 3) the androgen withdrawal phenomenon was discovered years after the trials were completed and patients were maintained on the antiandrogen much longer than is now known to be appropriate, 4) it failed to characterize the patients according to their risk of disease progression, and 5) the issue of duration of MAB was never discussed. • Although the overall benefit of MAB may be small, some patients will likely show a more substantial improvement in survival compared with androgen suppression alone. S22 VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY MAB for Advanced Prostate Cancer patients was 35 to 36 months and only in patients randomized to MAB. As a result, when physicians discuss the options for treating patients with metastatic prostate cancer, MAB should remain a reasonable option. Although the overall benefit may be small, a subset of patients, most likely those in a favorable risk group, will likely show a more substantial improvement in survival compared with androgen suppression alone. Many of those individuals may want to do everything possible to improve their outcome and may consider the benefits of the therapy to outweigh the cost and potential side effects. References 1. Huggins C, Hodges CV. The effect of castration, estrogens and androgen injection on serum acid phosphatase in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293-297. 2. 3. 4. 5. 6. 7. 8. 9. Trachtenberg J. Hormonal management of stage D carcinoma of the prostate. Urol Clin North Am. 1987;14:685-694. Labrie F, Dupont A, Belanger A. New hormonal therapy in prostatic cancer: combined treatment with an LHRH agonist and an antiandrogen. Clin Invest Med. 1982;5:267-272. Huggins C, Scott WW. Bilateral adrenalectomy in prostatic cancer: clinical features and urinary excretion of 17-ketosteroids and estrogen. Ann Surg. 1945;122:1031-1041. McLeod DG. Antiandrogenic drugs. Cancer. 1993;71:1046-1049. Brogden RN, Chrisp P. Flutamide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in advanced prostate cancer. Drugs Aging. 1991;1:104-115. Chodak GW, Sharifi R, Kasimis B, et al. Singleagent therapy with bicalutamide: a comparison with medical or surgical castration in the treatment of advanced prostate carcinoma. Urology. 1995;46:849-855. Crawford ED, Eisenberger MA, McLeon DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989;321:419-424. Janknegt RA, Abbou CC, Bartoletti R, et al. Orchiectomy and nilutamide or placebo as treatment of metastatic prostatic cancer in a multinational double-blind randomized trial. J Urol. 1993; 149:77-83. 10. 11. 12. 13. 14. 15. 16. 17. Dijkman GA, Janknegt RA, De Reijke TM, et al. Long-term efficacy and safety of nilutamide plus castration in advanced prostatic cancer, and the significance of early prostate specific antigen normalization. J Urol. 1997;158:160-163. Denis LJ, Keuppens F, Smith PH, et al. Maximal androgen blockade: final analysis of EORTC phase III trial 30853. Eur Urol. 1998;33:144-151. Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomized trials. Lancet. 2000;355:1491-1498. Sarosdy MF, Schellhammer PF, Sharifi R, et al. Comparison of goserelin and leuprolide in combined androgen blockade therapy. Urology. 1998; 52:82-88. 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. Kelly WK, Scher HI. Prostate specific antigen decline after antiandrogen withdrawal: the flutamide withdrawal syndrome. J Urol. 1993; 149:607-609. Sarosdy MF, Schellhammer PF, Johnson R, et al. Does prolonged androgen blockade have survival benefits over short-term combined androgen blockade therapy? Urology. 2000;55:391-395. Klotz L. Combined androgen blockade in prostate cancer: meta-analyses and associated issues. BJU Int. 2001;87:806-813. VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY S23