Advanced Prostate Cancer: An Update

Advanced Prostate Cancer:

10TH INTERNATIONAL PROSTATE CANCER UPDATE Advanced Prostate Cancer: An Update Ali Ziada, MD,* E. David Crawford, MD,† Fritz H. Schröeder, MD,‡ Martin E. Gleave, MD,§ Paul D. Miller, MD, FACP,† Marc B. Garnick, MD *Cairo University, Cairo, Egypt; †University of Colorado Health Sciences Center, Denver; ‡Erasmus University, Rotterdam, the Netherlands; §University of British Columbia, Vancouver; Harvard Medical School, Cambridge, Mass. A number of therapeutic options are available or on the horizon for patients for whom initial treatment of localized prostate cancer has failed. Currently under study are time of therapy, maximum androgen blockade, and palliative and adjunctive therapies. Key words: Androgen • Antineoplastic agents, hormonal • Prostate-specific antigen • Prostatic neoplasms P rostate cancer is the most frequently diagnosed cancer in the United States and the second most common cause of death in American males. In recent years, screening and early diagnosis of prostate cancer have attempted to improve survival; however, a large proportion of patients with initially localized disease progress. Both the definition and therapy of advanced prostate cancer are challenging. This article provides an overview of therapeutic options: dealing with a rise of prostate-specific antigen (PSA) level after initial therapy, minimal androgen blockade, timing of therapy, palliative and adjuvant therapy, and novel therapeutic options. Rising PSA After Failed Therapy Data from the National Cancer Database and from the experience of E. David Crawford, MD,1 reveal that of all patients who have prostate cancer, approximately 30% have been treated by radical prostatectomy, 30% by radiation therapy, 12% by hormonal treatment, and 7% by other forms of treatment, while 25% receive no treatment. These percentages add up to more than 100% because some patients received more than 1 form of therapy. Today, the most common presentation of advanced prostate cancer is the patient with a rising PSA level after local therapy has failed. New substages of advanced disease identify 2 groups in particular: those with a rising PSA level after failed local therapy (D1.5) and those with a rising PSA level after failed hormonal therapy (D2.5).2 It is generally accepted that after a radical prostatectomy, the PSA level should be below 0.2 ng/mL and after radiation therapy, below 0.5 ng/mL. A rise is an elevation in 3 consecutive PSA tests. Time to PSA nadir and recurrence as well as the pattern of PSA recurrence give some prognostic insights. Pretreatment Gleason grade and PSA level are still the most reliable predictors of failure. The evaluation of patients following definitive treatment, however, adds in- Supplement REVIEWS IN UROLOGY 35 Advanced Prostate Cancer continued formation that helps predict who will have a greater chance for treatment failure. The postprostatectomy evaluation may include biopsy of the surgical anastomosis, bone scan, pathologic review of surgical margin specimens, determination of the slope of the rise of the PSA level, and ProstaScint scan.3 Unfortunately, there are no reliable means of identifying recurrences limited to the pelvis. In addition, the falsenegative rate for ProstaScint scans remains high. New tools to evaluate outcomes will become important in the decisionmaking process. Neural networks can be applied to prostate cancer patient management because of their ability to detect hidden patterns in data. The networks can be used to predict treatment failure and to select high-risk cohorts for randomized trials. As our understanding of the cancer cell improves, many events that play additive or synergistic roles are being identified. The complex relations of the cell membrane and its adhesion molecules have been studied in recent years. The malignant cell must be able to change its ability to adhere to elements in its local environment in order to grow outside the confines of the glandular epithelium. E-cadherin is a protein on the cell surface that affects adherence. E-cadherin expression is decreased in highergrade prostate cancers.4 High E-cadherin expression is a positive prognostic sign and correlates inversely with Gleason grade and metastatic disease as well as disease progression. Although it is difficult to correlate E-cadherin expression with survival, the use of E-cadherin assays in the selection of high-risk cohorts seems logical. The decision to start treatment after failed prostatectomy or radiation therapy is controversial. Factors that must be considered include the likelihood that the disease was incurable initially, the possibility of cure after failure, and the patient’s life expectancy. The possibility of added morbidity must be understood by the patient as well. 36 REVIEWS IN UROLOGY Supplement Gibbons and associates5 have shown the usefulness of radiation therapy versus observation in T3 disease with respect to control of local recurrence; however, there was no survival advantage. Other authors have not been able to demonstrate a survival advantage using radiation therapy after prostatectomy. It has been postulated that PSAlevel decrease after radiation therapy may be mediated by decreased testosterone secondary to the radiation effects of scatter to the testis.6 Combination Finasteride/ Flutamide Therapy There is no gold standard of treatment for patients with advanced prostate cancer for whom local therapy has failed. Recent advances have been directed simultaneously at limiting the side effects experienced by the patient and controlling disease progression. In the past, the treatment of patients with metastatic prostate cancer frequently involved androgen deprivation therapy (ADT), which included bilateral orchiectomy or gonadotropin-releasing hormone (GnRH) agonist with or without antiandrogen therapy.7 Although this form of treatment is effective, patients frequently experience such side effects as anemia, hot flushes, GI disturbances, loss of libido, impotence, muscle wasting, osteoporosis, and changes in psychological state.8 In an attempt to find an alternative treatment with fewer side effects, investigators studied a combination of a 5-reductase inhibitor, finasteride (5 mg PO bid), with a low-dose antiandrogen, flutamide (125 mg PO bid), to treat patients for whom initial therapy failed and who presented with biochemical failure.9 These researchers examined the effects of this drug combination in 73 men treated at 2 separate institutions with a minimum of 3 months of follow-up. The investigators hypothesized that this treatment might control tumor growth and, at the same time, limit the side effects seen in patients undergoing complete androgen blockade. In theory, this drug combination should block dihydrotestosterone levels, the major androgen substrate of the prostate, while maintaining serum testosterone levels.10 The synergistic effect of this drug combination is a result of lowering the level of dihydrotestosterone (finasteride) and blocking its action at the receptor level (flutamide). The combination of finasteride with low-dose flutamide in this study led to tumor regression, as indicated by declining PSA levels. The mean followup of the patient population was 24.5 months and ranged from 3 to 54 months. Of the initial 73 patients, 26 continue on this drug combination, and follow-up is ongoing. Data analyzed are from these 73 patients and were gathered during the active treatment phase of the study. The flutamide and finasteride combination is associated with some of the ADT side effects, but to a lesser degree.11-14 The most frequently reported side effects were gynecomastia and breast tenderness. Two of the patients experienced hepatic dysfunction, as indicated by an elevation in liver function test (LFT) results, a well-documented side effect of flutamide. After 4 months, 1 patient with elevated LFT results was removed from the study and placed on an alternative hormonal regimen. The other withdrew after approximately 24 months and started on a different hormonal regimen. Although the results demonstrate the effectiveness of this drug combination with minimal side effects, this information is based on a relatively short period of observation and follow-up. Based on the results seen when the flutamide dose was increased to 750 mg, this regimen does not seem to hasten the development of hormone resistance. This possibility, however, needs further evaluation in a randomized study. The selection of an ideal patient population for this type of treatment is difficult. Quality-of-life issues are a key concern for patients who have less advanced prostate cancer or for pa- Advanced Prostate Cancer tients who want treatment after radical therapies have failed. Those with more advanced prostate cancer tend to place more importance on quality of life. The lead time that PSA determination offers enables use of therapy that promises longer duration of tumor regression. Early Versus Delayed Therapy Hormonal therapy has become standard for symptomatic men with metastatic disease. This treatment is more controversial for patients with stable disease and no symptoms. Hormonal deprivation timing in the latter group is debatable. Deferred hormonal therapy was generally the rule after the publication of studies by the Veterans Administration Cooperative Urological Research Group (VACURG).15 Delayed treatment was encouraged, because these studies showed no survival benefit from early hormonal manipulation. Furthermore, the use of early hormonal therapy was believed to alter the nature of metastatic lesions, resulting in earlier development of hormone refractory disease. An update of the VACURG study in 198816 determined that disease progression from stage C to stage D was decreased from 50% to 10% with diethylstilbestrol therapy. Crawford and associates17 also showed a benefit of early hormonal therapy in patients with distant metastasis. The patients randomly assigned to receive leuprolide and flutamide had a longer progression-free survival and an increase in the median length of survival, compared with those who received placebo. In 1997, the Medical Research Council18 published results of a randomized study of 938 patients with locally advanced or asymptomatic metastatic prostate cancer. Patients received immediate treatment with either orchiectomy or GnRH hormone agonist or received the same treatment deferred until symptoms occurred. Overall survival was significantly prolonged in the patients treated early. Quality of life was improved in the early treatment group. Extraskeletal metastases, pathologic bone fractures, spinal compression, and ureteric obstruction were significantly reduced for patients in this group, compared with patients in the deferred treatment group. Laboratory studies have shown that early hormonal therapy does not result in earlier androgen resistance.19 The value of early ADT lies in prolongation of disease-free survival and, hence, improvement in the quality of life. A final conclusion awaits further studies. Intermittent Androgen Suppression The role of androgen withdrawal is well established in the treatment of patients with advanced prostate cancer. Indications for androgen withdrawal therapy have expanded beyond newly diagnosed metastatic disease to encompass localized disease with a high risk of systemic relapse and biochemical failure as the only manifestation of recurrent disease after local therapy. Earlier intervention raises the prospect of long periods of ADT attended by clinical side effects that reduce quality of life. Early on, androgen withdrawal results in hot flushes, loss of libido, impotence, and general fatigue. Long-term castration leads to bone demineralization, anemia, lipid disorders, and muscle wasting. Most important: biologic processes, such as the up-regulation of previously androgenrepressed survival genes, result in the emergence of androgen-independent growth. Gleave20 recently reviewed the longterm follow-up results of a prospective phase II evaluation of intermittent androgen suppression in the treatment of patients who have prostate cancer. A total of 87 patients have been entered into this protocol, of whom 50 have been followed for a minimum of 3 years. Treatment was initiated with combined androgen blockade and continued for at least 6 months until a serum PSA nadir was observed. Medication was then withheld until the serum PSA level increased to mean values of between 10 and 20 ng/mL. This cycle of treatment/no treatment was repeated until the regulation of PSA became androgen independent. The total time in the study ranges from 40 to 126 months, with a mean of 65.5 months. The average time (percentage) off therapy for cycles 1, 2, 3, and 4 was 15 months (54%), 10 months (48%), 8 months (45%), and 7 months (40%), respectively. The study group included 9 patients treated because of a rising PSA level following radiation therapy for locally advanced cancer. These patients have been off therapy for an average of 22 and 13 months in the first 2 treatment cycles, respectively. Six patients with rising PSA levels following radical prostatectomy and with follow-up exceeding 36 months have been off therapy for an average of 19 and 11 months in the first 2 treatment cycles, respectively. Twentythree (26%) of 87 patients have progressed to androgen independence. The mean time to androgen independence was 40 months (median, 32 months; range: 14 to 62 months). Fourteen of these 23 patients had metastatic disease at initiation of treatment, 12 with D2 and 2 with D1 cancer. The mean and median times to androgen-independent progression in the 12 stage D2 men were 35 and 31 months, respectively. Their overall survival was 50 months (median, 42 months). After interruption of the first and second treatment cycles, serum testosterone recovered to at least 50% of baseline value in 56 (97%) of 58 and 21 (91%) of 23 men, respectively. This rise in testosterone was associated with an improvement in sense of well-being and recovery of libido and potency in men who reported normal or near-normal sexual function before the start of therapy. The average time for testosterone recovery into the normal range was 19 and 18 weeks in the first and second cycles, respectively. Prostate cancer is amenable to control by intermittent androgen suppres- Supplement REVIEWS IN UROLOGY 37 Advanced Prostate Cancer continued sion. This approach affords an improved quality of life when the patient is off therapy, with reduced toxicity and costs. Phase II trials suggest that there is not a negative impact on patient outcome. Randomized, prospective protocols are currently under way to determine whether survival is affected in a beneficial or adverse way in men with locally recurrent or metastatic cancer. Bisphosphonates Adjuvant Therapy Bisphosphonates have recently been used to prevent and manage the following disorders in men: glucocorticoid-induced osteoporosis, age- or hypogonadal-related osteoporosis, and known skeletal metastases or multiple myeloma.21 Investigational studies are now under way to determine the possible role of bisphosphonates in the prevention of skeletal metastases in men with prostate cancer. The number of men in whom osteoporosis develops is increasing, mainly because of increased life span. Most men begin to lose bone mass around age 65, independent of gonadal status. Age-related bone loss has a pathophysiology that is not related to gonadal hormone function. Hypogonadal men (those who have had surgical or medical androgen ablation) lose bone mass from the time of gonadal ablation. The only objective means of identifying men who are at risk for osteoporotic fractures is the measurement of bone mineral density (BMD). Men with a low BMD at the time of androgen ablation have a higher risk of bone fracture than have those whose BMD is normal or high at the time of androgen ablation.21 The lifetime risk of hip or vertebral fracture from osteoporosis is lower in white men than in white women, because men have a higher peak bone mass than women do. Lifetime fracture risk in men is not insignificant (8% for hip and 20% for vertebral fracture),21 and this risk is increasing as men live longer. 38 REVIEWS IN UROLOGY Supplement The number of men at risk for osteoporosis as a result of some form of androgen ablation is expected to increase as PSA screening identifies prostate cancer in a greater percentage of men. Recent data show that the bisphosphonate alendronate (10 mg/d) can increase BMD in elderly men, regardless of their gonadal status. In alendronate trials, the men studied had either a prevalent vertebral fracture or a T-score (the SD reduction in BMD below the young male normal reference range) of 2 SD or lower. Alendronate, at this same dose, has recently been approved for the prevention and/or management of steroidinduced osteoporosis in men and women. Patients receiving either “highdose” corticosteroids (ie, those used in transplantation or polymyalgia rheumatica) or “low-dose” prednisone or other glucocorticoid-dose equivalents (7.5 mg/d for 3 months or longer) are candidates for alendronate administration. There are currently no guidelines in the United States for screening men at risk for osteoporosis, but it is likely that such guidelines will be developed in the near future. Certainly, men who are hypogonadal should be considered for BMD testing, and if their BMD is low (below 2 SD), or if they have already sustained fragility fractures, they should be considered for bisphosphonate therapy. The bisphosphonate pamidronate is approved for treating patients with Paget disease, combating the hypercalcemia of malignancy, and reducing the risk of fractures in patients with metastatic skeletal disease or multiple myeloma.21 The use of pamidronate (90 mg IV per month) for at least 2 years improves the quality of life in these patients. Patients treated with pamidronate should have adequate renal function and adequate vitamin D/calcium intake. Their parathyroid function should be assessed before infusion to avoid symptomatic hypocalcemia or the exacerbation of chronic renal disease. Patients with known skeletal metastasis should be considered for this bisphosphonate intervention. Clinical trials are currently under way to investigate the use of bisphosphonates to prevent tumor cells from establishing residence in bone. The bisphosphonates, in various in vitro and in vivo animal models, have been shown to inhibit tumor cell (breast and prostate) adherence to bone matrix and induce apoptosis in tumor cells (as well as in osteoclasts and osteocytes).22 A large clinical trial is under way to test the ability of a very potent bisphosphonate, zoledronate, to prevent skeletal metastasis in men with nonmetastatic prostate cancer.22 This prospective, randomized, placebo-controlled trial is enrolling prostate cancer patients with no previous evidence of skeletal metastasis. One group will receive monthly zoledronate and the other group, placebo. Both groups will have frequent bone scans and other appropriate tests. Any patient in whom evidence of skeletal metastasis is detected will automatically be placed in the active zoledronate treatment arm. If results of this scientific study are positive and zoledronate prevents skeletal metastasis, then subsequent FDA approval for this indication would make this treatment widely available for men. Novel Treatments for Advanced Prostate Cancer The efficacy of medical or surgical castration for the management of prostate cancer has been well documented. Over the years, different forms of medical hormonal therapy have been developed to enhance their effectiveness in achieving medical castration and/or to overcome safety issues. In the mid1980s, GnRH agonists were made available. Administration of GnRH agonists causes an initial surge of gonadotropins and other biochemical markers such as testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and PSA. The surge may last for 2 to 4 weeks before medical castration is achieved. The surges Advanced Prostate Cancer with GnRH agonists and delay in achieving castration are caused by an initial stimulation of GnRH receptor before receptor desensitization. These surges may be associated with deleterious clinical effects, such as exacerbation of urethral blockage and spinal cord compression.23 Because of the surge, antiandrogens often must be coadministered with GnRH agonists, resulting in additional side effects, compliance issues, and out-of-pocket expenses. A pure GnRH antagonist administered as a single agent that had a direct and immediate effect on the gonadotropin receptor would not cause this initial androgen stimulation and might eliminate the need for antiandrogens and their specific side effects. Abarelix depot represents the first depot in a new class of hormonal therapy—GnRH antagonists—and has been shown to be safe and effective in patients with prostate cancer.24 Studies to date with abarelix depot evaluated the endocrinologic achievement of medical castration (testosterone level of 50 ng/dL or less); biochemical efficacy (rate of PSA level decline); and magnitude of testosterone, LH, FSH, and PSA surge in contrast to GnRH agonists with or without antiandrogens. The results of these early studies demonstrated that abarelix depot induces a rapid fall in testosterone and PSA levels and achieves medical castration within 24 hours after a single intramuscular injection. Administration of this agent is devoid of the gonadotropin and biochemical surge seen during the first weeks of GnRH agonist treatment. Abarelix depot demonstrated an acceptable safety profile, with adverse events primarily limited to those associated with the disease and age of the patients.24 The analysis of the safety and the biochemical and endocrinologic efficacy of abarelix depot suggests that, as monotherapy, it may serve as an alternative to both medical and surgical methods of androgen ablation. Because of the lack of surge, abarelix depot may offer substantial advantage over existing hormone therapy for patients with prostate cancer in whom hormone ablation is required. Further research is currently being conducted in the use of abarelix depot for the management of prostate cancer. ■ References 1. Crawford ED. Advanced disease. Paper presented at: 10th International Prostate Cancer Update; February 2-6, 2000; Vail, Colo. 2. Crawford ED, Blumenstein BA. Proposed substages for metastatic prostate cancer. Urology. 1997;50:1027-1028. 3. Petronis JD, Regan F, Lin K. Indium-111 capromab pendetide (ProstaScint) imaging to detect recurrent and metastatic prostate cancer. Clin Nucl Med. 1998;23:672-677. 4. Umbas R, Isaacs WB, Bringuier PP, et al. Decreased E-cadherin expression is associated with poor prognosis in patients with prostate cancer. Cancer Res. 1994;54:3929-3933. 5. Gibbons RP, Cole BS, Richardson RG, et al. Adjuvant radiotherapy following radical prostatectomy: results and complications. J Urol. 1986;135: 65-68. 6. Grigsby PW, Perez CA. The effects of external beam radiotherapy on endocrine function in patients with carcinoma of the prostate. J Urol. 1986;135:726-727. 7. Crawford ED. Changing concepts in the management of advanced prostate cancer. Urology. 1994; 44(suppl):67. 8. Karling P, Hammar M, Varenhorst E. Prevalence and duration of hot flashes after surgical or medical castration in men with prostatic carcinoma. J Urol. 1993;23:106. 9. Lisle T, Mackenzie S, Ziada A, et al. Androgen deprivation therapy using finasteride and low dose flutamide to treat PSA failure following therapy for clinically localized adenocarcinoma of the prostate (CaP). J Urol. 1999;161:4(suppl):299. Abstract 1151. 10. Fleshner N, Trachtenberg J. Sequential androgen blockade: a biological study in the inhibition of prostate growth. J Urol. 1992;148:1928. 11. Brufsky A, Fontaine-Rothe P, Berlane K, et al. Finasteride and flutamide as potency sparing androgen-ablative therapy for advanced adenocarcinoma of the prostate. Urology. 1997;49:913-920. 12. Fleshner NE, Trachtenberg J. Treatment of advanced prostate cancer with the combination of finasteride plus flutamide: early results. Eur Urol. 1993;24(suppl 2):106-112. 13. Gormley G. Evaluation of men on finasteride. Semin Urol Oncol. 1996;14:139-144. 14. Ornstein DK, Rao GS, Johnson B, et al. Combined finasteride and flutamide therapy in men with advanced prostate cancer. Urology. 1996;48:901905. 15. Byar DP. Proceedings: the Veterans Administration Cooperative Urological Research Group’s studies of cancer of the prostate. Cancer. 1973; 32:1126-1130. 16. 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. 17. 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. 18. The 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;79:235-246. 19. Isaacs JT. The timing of androgen ablation therapy and/or chemotherapy in the treatment of prostatic cancer. Prostate. 1984;5:1-17. 20. Gleave ME. Intermittent androgen suppression. Paper presented at: 10th International Prostate Cancer Update; February 2-6, 2000; Vail, Colo. 21. Miller PD. Management of osteoporosis. Adv Intern Med. 1999;44:175-207. 22. Miller PD. Bisphosphonates: adjuvant therapy for prostate cancer. Paper presented at: 10th International Prostate Cancer Update; February 2-6, 2000; Vail, Colo. 23. Garnick MB. Hormonal therapy in the management of prostate cancer. Mol Urol. 1999;3:175182. 24. Garnick MB. Novel treatments for advanced prostate cancer: the new paradigm. Paper presented at: 10th International Prostate Cancer Update; February 2-6, 2000; Vail, Colo. Supplement REVIEWS IN UROLOGY 39