Prostate Cancer Update: Advanced Disease

13TH INTERNATIONAL PROSTATE CANCER UPDATE Prostate Cancer Update: Advanced Disease Michael A. Carducci, MD Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins University, Baltimore, MD Additional Contributors E. David Crawford, MD, Celestia S. Higano, MD, Arturo Mendoza-Valdes, MD, Daniel P. Petrylak, MD, Jack Schalken, PhD The presentations for the “Advanced Disease" section of the 13th International Prostate Cancer Update provided an overview of current and future directions in the management of men with recurrent prostate cancer after local therapy and those with metastatic disease. Definitions of biochemical failure after local therapy were reviewed. Treatment strategies that were discussed included salvage radiation, early/intermittent hormonal therapy, cytotoxic chemotherapy, the use of bisphosphonates, and gene therapy. Several possible molecular targets for prostate cancer treatment need further validation before testing in clinical trials, and examples of these were presented. Each presentation focused on the need to accrue men to clinical trials to enable progress at a faster pace. [Rev Urol. 2003;5(suppl 6):S47-S53] © 2003 MedReviews, LLC Key words: Androgen deprivation • Intermittent hormonal therapy • Targeted therapies • Bisphosphonates • Docetaxel • Calcitriol • Gene regulation t the “Advanced Disease" session of the 13th International Prostate Cancer Update, a range of topics were reviewed. The presentations (and presenters) were as follow: “Is There a Role for Early Therapy in Biochemical Failures?" (E. David Crawford, MD); “Intermittent Hormonal Therapy" (Arturo Mendoza-Valdes, MD); “New Targets for Therapy: A Critical Appraisal" (Jack Schalken, PhD); “Exciting Developments in Chemotherapy" (Daniel P. Petrylak, A VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY S47 Advanced Prostate Cancer continued MD); “Role of Bisphosphonates in Prostate Cancer" (Celestia S. Higano, MD); and “Gene Re-expression as a Therapeutic Strategy in Prostate Cancer" (Michael A. Carducci, MD). This set of presentations provided an excellent overview of current and future directions in the management of men with recurrent prostate cancer after local therapy and those with metastatic disease. Is There a Role for Early Therapy in Biochemical Failures? In this lecture, Dr. Crawford, from the University of Colorado Health Sciences Center, discussed many of the controversies associated with the management of men with biochemical failure after local therapy. Supported by published data and clinical experience, Dr. Crawford put forth his views regarding early therapies for patients who present with an elevated prostate-specific antigen (PSA) level after radical prostatectomy or definitive radiation therapy.1 According to the nomenclature or the disease classification suggested by Drs. Crawford and Blumenstein,2 these patients are classified as D1.5, which suggests that they likely have micrometastatic disease that is not detectable by standard radiographic studies. All of these patients proceed to progressive metastatic disease if they live long enough. Dr. Crawford estimates that approximately 53,600 men fall into this category each year. The management of these patients requires a rigorous review of the literature and frank discussions with patients regarding the significance of an elevated PSA level after local therapy. Dr. Crawford examined the threshold for defining failure after local therapy. In most postsurgical studies, a PSA level of greater than 0.4 ng/mL constitutes recurrence. The Pound data3 from Johns Hopkins University suggested that median survival for a S48 VOL. 5 SUPPL. 6 2003 patient with a PSA recurrence after prostatectomy was approximately 13 years and that men with higher Gleason scores (Gleason 8–10), shorter PSA doubling times (<10 months), and first PSA elevation within 2 years of surgery have the greatest likelihood of early metastatic disease and death. The American Society for Therapeutic Radiology and Oncology definition of recurrence after radiation remains three consecutive rises in the PSA level after a post-therapy nadir has been reached. This definition of recurrence is the same for patients undergoing brachytherapy as for those undergoing primary therapy, with a caution that a subset of brachytherapy patients might experience a “PSA bounce" that does not indicate recurrence. Postprostatectomy patients with a PSA recurrence should be evaluated for clinically localized recurrences that might be treatable with salvage radiation. Patients who are less likely to benefit from salvage radiation include those who had extensive disease at the time of surgery (seminal vesicle or lymph node involvement), those with a PSA level greater than 1.5 ng/mL preradiation, and those with a short PSA doubling time or PSA levels that rise within the first year postsurgery. In many instances, when these men are irradiated, androgen deprivation therapy is initiated as well. Men unlikely to benefit from salvage radiation and those with radiation as their primary therapy might be considered for early hormonal therapy (complete androgen blockade [CAB], monotherapy with a luteinizing hormone-releasing hormone agonist, or other hormonal manipulations, including high-dose bicalutamide or agents such as finasteride) or watchful waiting. Early hormonal therapy for patients with biochemical relapse has its proponents, including Dr. Crawford. He REVIEWS IN UROLOGY cited clinical data from the European Organization For Research and Treatment of Cancer trial led by Bolla,4 Radiation Therapy Oncology Group study 8610, the Eastern Cooperative Oncology Group, and the Medical Research Council that suggest that early use of hormonal therapy benefits patients by delaying time to first metastases, by delaying the onset of clinical symptoms, and possibly by prolonging survival.1,5 Dr. Crawford reviewed the Shionogi mammary tumor model as a laboratory study, implying that early hormonal therapy should have a greater impact on men with biochemical failures. The negative aspects of hormonal therapy, including its effects on quality of life, were briefly mentioned. Dr. Crawford gave his definition of the acronym “PSA" as “patient-stimulated anxiety," to suggest that patients want and expect therapy for their recurrent disease. In closing, Dr. Crawford discussed adjuvant clinical trials in which chemotherapy is used in conjunction with androgen deprivation for men at high risk for relapse after local therapy. He described Southwest Oncology Group (SWOG) study 9921 as a large cooperative group trial seeking to enroll 1260 men at high risk for relapse for randomization to complete androgen deprivation with or without mitoxantrone and prednisone. This study remains open and is a national priority. Dr. Crawford reaffirmed that he strongly advocates encouraging men to participate in clinical trials and that greater cooperation among urologists and medical oncologists is required to complete important studies addressing questions such as those proposed by SWOG 9921. The Role for Intermittent Hormonal Therapy Dr. Mendoza-Valdes of Instituto Nacional de Ciencias Medicas y Advanced Prostate Cancer Nutricion Salvador Zubiran, provided a clear and concise review of the current status of intermittent hormonal therapy. In his opening comments, he reviewed the objectives of androgen deprivation, specifically CAB. Despite the benefit of CAB (induction of prostate cancer cell apoptosis, 80% objective response rates, and a mean time to progression of approximately 24 months), CAB is costly, and most patients follow-up of patients receiving intermittent hormonal therapy of 30.8 months, a median cycle length of 9 months, percent time off hormonal therapy at 59.6%, and an estimated 3year time to clinical progression. Ongoing clinical trials exploring the role of intermittent hormonal therapy were reviewed. The first study reviewed was the IAB TULP (Intermittent Androgen Blockade– Therapy Upgrading Life in Prostate There remains controversy as to which patients might benefit the most from intermittent hormonal therapy, when to start hormonal therapy, how long to treat before stopping, and when to restart subsequent cycles. demonstrate a rise in PSA level in 2 years, experience significant lifealtering adverse effects, and have an uncertain improvement in survival. Adverse effects of androgen deprivation are impotence, loss of libido, loss of facial hair, loss of muscle mass, and mood changes, to name a few.6 Antiandrogens, such as flutamide and bicalutamide, have nausea, vomiting, diarrhea, and gynecomastia as potential negative effects. Intermittent hormonal therapy might have some advantages over CAB.7 Dr. Mendoza-Valdes reviewed the benefits of intermittent androgen deprivation: it demonstrates fewer side effects and a better quality of life, has the potential to increase androgen dependence or responsiveness, and can significantly reduce costs because medication dosing and frequency are reduced. In summarizing the reported literature, Dr. Mendoza-Valdes suggested that the mean cycle length ranges from 5 to 18 months, with much of the heterogeneity resulting from different definitions of when the hormonal agents should be started and stopped. He reviewed the recent Clinical Prostate Cancer article by de Leval et al that demonstrated a mean Cancer) and the second is the ongoing SWOG study of intermittent hormonal therapy for men with metastatic disease. In each of these studies, the preliminary suggestions are that there is an improvement in quality of life, reduced adverse effects, and reduced costs for the intermittent therapy approach. Despite these early results, there remains controversy as to which patients might benefit the most, when to start hormonal therapy, how long to treat before stopping, and when to restart subsequent cycles. The SWOG and IAB TULP studies will assist in answering some of these questions. New Targets for Therapy: A Critical Appraisal Dr. Jack Schalken, of Nijmegen University, demonstrated his leadership in the field of molecular target assessment throughout his thoughtprovoking lecture. He started by expressing concern over the way therapeutic targets are evaluated. Dr. Schalken hypothesized that the “Achilles heel" of the prostate cancer cell might lie among a list of targets that include the following: the androgen axis (specific androgen receptor modulators); growth factor response inhibitors (epidermal growth factor receptor [EGFR], HER2, tyrosine kinase [TRK]); telomerase inactivation; invasion/metastasis inhibitors (de-differentiation, proteases); and prostate cancer–specific gene expression (gene therapy). Although each of these targets represents a single approach, most are redundant, and effects might be at a specific receptor or at molecules downstream in a signal transduction pathway. He also expressed the need for an improved understanding of cancer cell–host interactions. From studying these interactions, one might be able to develop better agents that target stroma–epithelial interactions and angiogenesis or identify cell membrane antigens for targeting by antibodies or vaccines. Citing 3 examples of targets that need further validation before clinical trial testing, Dr. Schalken reminded the participants that all cancer cells are not equal and that we might be better off if we determine what cell type we are targeting. His first example was the search for the prostate cancer stem cell as the hierarchal target (ie, the most undifferentiated cell).8 Dr. Schalken asked: Using three distinct keratins and c-met expression, can these features identify the prostate cancer stem cell? Hypotheses continue to be generated regarding cancer stem cells, and the question remains whether the stem cell should be found and targeted or whether a target essential to the maintenance of the stem cell itself could be identified. In a second example, Dr. Schalken supported ongoing study of the androgen receptor. In advanced disease there is ligand depletion, and androgen receptor antagonists have limited efficacy. Despite androgen deprivation, the androgen receptor and its downstream effects remain intact. His research laboratory and VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY S49 Advanced Prostate Cancer continued Table 1 Single-Agent Taxane Chemotherapy for Prostate Cancer Agent Paclitaxel13 Dose 135–170 mg/m IV over 24 h every 3 wk 2 Paclitaxel14 Docetaxel15 Docetaxel16 150 mg/m IV weekly  6 wk then 2 wk off 75 mg/m IV every 21 d 36 mg/m2 IV weekly  6 wk then 2 wk off 2 2 N 23 18 35 25 Response* 4.3% 39% 46% 46% Median survival time 9 mo 13.5 mo 12 mo 10 mo Major toxicity† 74% neutropenia 2 deaths 17% neutropenia 43% neutropenia 35% neuropathy 2 deaths 25% neutropenia *Percent with >50% prostate specific antigen decline. † Grade 3 or greater. others are using deoxyribonucleic acid (DNA) microarrays to identify (through high-throughput screens) novel targets working through or downstream of the androgen receptor. His third example comes from studies of the molecular profiles of advanced cancers, which demonstrate that other receptors, such as EGFR or TRKa (TRK A receptor), are overexpressed in prostate cancer. Agents such as Iressa or Tarceva are available to target EGFR, and CEP701 might target TRKa receptors. With the coming availability of small molecules to target cancer, we might be moving toward an individualized approach to treating prostate cancer, in which multiple agents are selected for a patient based on molecular profiling of the cancer at diagnosis, thus providing better interference with prostate cancer cell growth pathways. Exciting Developments in Chemotherapy Dr. Daniel P. Petrylak, of New York Presbyterian Medical Center, summarized recent results and advances with the use of cytotoxic chemotherapy for advanced disease. Hormone-refractory prostate cancer now includes a wide spectrum of patients, from men S50 VOL. 5 SUPPL. 6 2003 with rising PSA levels as the only sign of progression (despite their having castrate-level testosterone) to men with symptomatic, progressive, metastatic hormone-refractory disease. The latter group is the one in which most chemotherapy agents have been used in the management of advanced disease. The taxanes are currently the antitumor agents most widely used after progression on hormonal therapy. Docetaxel and paclitaxel each have single-agent activity in men with hormone-refractory disease, demonstrating greater than the every-3-week schedule, whereas nail bed changes and excessive tearing from lacrimal duct obstruction are more common on the weekly schedules. Estramustine has commonly been added to the taxanes for a combination treatment strategy. Combination studies of docetaxel and estramustine demonstrate PSA declines of greater than 50% in more than 65% to 75% of patients, with mean time to progression in the range of 20 to 26 weeks and median survival of 20 to 23 months (Table 2). In each of the published studies, it appears that the responders have a better outcome, and now combination chemotherapy induces clinical responses more often than not. SWOG 9916 recently completed accrual, with more than 740 patients with metastatic, hormone-refractory prostate cancer. SWOG 9916 is a randomized trial of mitoxantrone and prednisone versus docetaxel and estramustine. The study is powered to demonstrate a 33% improvement in survival for the docetaxel/estramustine arm over the mitoxantrone/ prednisone arm. Dr. Petrylak reviewed the recently published phase 2 data from the Oregon Health & Science University Hormone-refractory prostate cancer now includes a wide spectrum of patients, from men with rising PSA levels as the only sign of progression to men with symptomatic, progressive, metastatic hormone-refractory disease. 50% declines in PSA levels in approximately 45% of men receiving the agents (Table 1). Docetaxel, a depolymerizing microtubule agent, can be administered on a weekly or every-3-week schedule and maintain clinical activity. Toxicity to singleagent docetaxel is relatively mild, with fatigue being the most common adverse effect that patients will experience. Neutropenia is greater on REVIEWS IN UROLOGY study in which docetaxel was used in combination with calcitriol. In this study, Beer and colleagues9 demonstrated that the combination lowered the PSA by 50% in 81% of patients and showed a median survival of 19 months. There were no significant episodes of hypercalcemia when the calcitriol was administered once weekly with the weekly docetaxel. In other data, the National Cancer Advanced Prostate Cancer Table 2 Chemotherapy Combinations of Taxanes and Estramustine Phosphate (EMP) Agents EMP + Paclitaxel17 EMP + D18 EMP19 Dose EMP 280 mg po bid days 1–3 P 90 mg/m2 IV weekly  6 wk every 8 wk EMP 280 mg po tid days 1–5 D 70 mg/m2 IV day 2 Repeats every 3 wk EMP 10 mg/kg/d po days 1–5 D 70 mg/m2 IV day 2 Dex 8 mg po bid days 1–3 H-cort 30 mg/d N 63 35 47 (46 evaluable) Response* 58% 74% 68% Median survival time 17.2 mo 77% alive at 12 mo 20 mo Major toxicity 6% neutropenia 6% vascular 1 toxic death 63% neutropenia 12% vascular 2 toxic deaths 56% neutropenia 6% vascular † D, docetaxel; Dex, dexamethasone; H-cort, hydrocortisone. *Percent with >50% prostate specific antigen decline. † Grade 3 or greater. Institute reported their randomized, phase II study of docetaxel with or without thalidomide. The number of patients demonstrating a PSA decline of 50% or greater was 51% for the combination and 37% for single-agent docetaxel. In the thalidomide/docetaxel arm, 69% of the patients were alive at 18 months, compared with 47% of the patients in the docetaxel-alone arm.10 These phase II studies combining docetaxel with other biologic, nonestramustine agents, with their encouraging results, will likely provide the next comparator arm to the winner of SWOG 9916. The Role of Bisphosphonates in Prostate Cancer Dr. Celestia S. Higano, Associate Professor of Medicine at the University of Washington, began her lecture with a succinct overview of bone metabolism and the biology of bone metastasis. In prostate cancer, prostate cancer cells stimulate osteoblasts by various secreted growth factors. Osteoclasts are inhibited as a result, which in turn results in a concentrate of newly formed bone. The bisphosphonates alter this osteoblast–osteoclast interaction. In breast cancer and multiple myeloma, the bisphosphonates (primarily pamidronate) demonstrated reduction in skeletal related events. Data incorporating bisphosphonates into the management of prostate cancer have mostly been negative to date, with the events (pain, fracture, need for radiation, cord compression) than placebo. Thirty-eight percent of patients receiving zoledronate had a skeletal related event, as compared with 48% of patients taking placebo, and the median time to first skeletal related event was significantly longer with zoledronate than with placebo (488 vs 321 days). Patients taking zole- In breast cancer and multiple myeloma, the bisphosphonates (primarily pamidronate) demonstrated reduction in skeletally related events. exception of zoledronate, a newer, more potent bisphosphonate. Dr. Higano reviewed the study that led to the US Food and Drug Administration approval of zoledronate for men with metastatic prostate cancer.11 Prior studies with bisphosphonates were underpowered, used bisphosphonates with poor bioavailability and low potency, and studied patients with active pain syndromes. Zoledronate at 4 mg IV over 15 minutes every 3 weeks demonstrated fewer skeletal related dronate had a lower skeletal morbidity rate and lower pain scores throughout the course of the study. Despite these clinically significant benefits, there was no difference in time to progression in bone, in disease, or in survival, which suggests that zoledronate at the 4-mg dose might have little direct antitumor effect. Gene Re-Expression as a Therapeutic Strategy for Prostate Cancer Dr. Michael A. Carducci, of The Johns VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY S51 Advanced Prostate Cancer continued Table 3 Known Genes Silenced by Promoter Methylation in Prostate Cancer Progression Glutathione S-transferase  Androgen receptor Retinoic acid receptor ß Neutral endopeptidase p16 Estrogen receptor Endothelin B receptor E-cadherin Hopkins University School of Medicine, closed the afternoon session by reviewing a novel strategy focused on re-expressing reversibly silenced genes in malignant cells. Methods of gene inactivation include genetic events, such as mutations or deletions. However, epigenetic changes, heritable traits that are mediated by changes in DNA other than nucleotide sequences, are now thought to play an important role in gene expression. Two epigenetic events that have been associated with transcriptional silencing include methylation of CpG islands located in gene promoter regions of cancer cells and changes in chromatin conformation involving histone acetylation. Recent evidence demonstrates that these processes work synergistically to form “layers" of genetic silencing. Reversal of these function of the re-expressed gene(s). 5-azacytidine (5-AC) is a cytosine analogue that has been shown to demethylate DNA with resultant effects on gene expression and cell differentiation. Once 5-AC is incorporated into DNA, a marked dose-dependent and time-dependent decrease (>95%) in DNA methyltransferase activity occurs. Table 3 Reversal of epigenetic processes has become a new therapeutic target in cancer treatment. epigenetic processes and up-regulation of genes important to prevent or reverse the malignant phenotype have therefore become new therapeutic targets in cancer treatment. Inhibition of methyltransferase, the enzyme that catalyzes the methylation of CpG islands of gene promoter regions, leading to transcriptional silencing, promotes expression of previously silenced genes in vitro. The clinical implication of methyltransferase inhibition depends on the lists genes that are known to be methylation silenced in prostate cancer and are therefore targets for re-expression by the clinical application of 5-AC in patients with prostate cancer. Inhibitors of histone deacetylase are another class of small molecules under study to re-express silenced genes.12 Acetylated histones maintain chromatin in an open reading frame so that transcription can occur, whereas deacetylation of the his- Main Points • Patients who are less likely to benefit from salvage radiation include those who had extensive disease at the time of surgery, those with a prostate-specific antigen (PSA) level greater than 1.5 ng/mL preradiation, and those with a short PSA doubling time or PSA levels that rise within the first year postsurgery. • Clinical data suggest that early use of hormonal therapy benefits patients by delaying time to first metastases, by delaying the onset of clinical symptoms, and possibly by prolonging survival. • Intermittent hormonal therapy might have some advantages over complete androgen blockade: it demonstrates fewer side effects and a better quality of life, has the potential to increase androgen dependence or responsiveness, and can significantly reduce costs. • Combination studies of docetaxel and estramustine demonstrate PSA declines of greater than 50% in more than 65% to 75% of patients, with a median survival of 20 to 23 months; docetaxel in combination with calcitriol lowered PSA by 50% in 81% of patients and showed a median survival of 19 months. • A randomized, placebo-controlled trial of zoledronate for men with metastatic prostate cancer showed that zoledronate demonstrated fewer skeletally related events (pain, fracture, need for radiation, cord compression) than placebo. • With the coming availability of small molecules to target cancer, we might be moving toward an individualized approach to treating prostate cancer, in which multiple agents are selected for a patient based on molecular profiling of the cancer at diagnosis. • A novel cancer treatment strategy focuses on re-expressing reversibly silenced genes in malignant cells; restoration of gene expression potentially results in restoration of gene function, resulting in re-establishment of normal cellular functions and tumor cell growth inhibition and death. S52 VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY Advanced Prostate Cancer tones forces the chromatin into a closed, tightly wound structure prohibiting ongoing transcription. Inhibitors of histone deacetylase maintain chromatin in the acetylated state to facilitate gene transcription. Gene products like the retinoic acid receptor are regulated by alterations in histone states. Retinoid resistance in prostate cancer might be a direct result of altered histone regulation. Small molecules that inhibit histone deacetylase seem to restore retinoid responsiveness in prostate cancer models, allowing for growth inhibition with the addition of a retinoid that is enhanced when co-administered with a cytotoxic like docetaxel or paclitaxel. Dr. Carducci described an ongoing phase 1 clinical trial at the Kimmel Cancer Center in which an inhibitor of DNA methyltransferase (5-AC) is combined with an inhibitor of histone deacetylase (sodium phenylbutyrate) in an effort to maximize gene re-expression of silenced genes. Restoration of gene expression potentially results in restoration of gene function, with the end result being a re-establishment of normal cellular functions and tumor cell growth inhibition and death. Conclusion The session entitled “Advanced Disease" explored exciting and controversial areas in the management of advanced prostate cancer. The talks were filled with hope and optimism that continued research into defining new targets, advancing chemotherapy, and improving palliation will lead to dramatic improvements in the survival and quality of life of men with recurrent prostate cancer. Each of the talks focused on the need to accrue men to clinical trials so that answers can be found more quickly and progress can be made at a faster pace. The session also demonstrated the multidisciplinary approach to the management of advanced prostate cancer and that urologists, radiation oncologists, medical oncologists, and basic translational scientists need to work together more closely to achieve the goal of improved care for and the cure of men with prostate cancer. 9. 10. 11. 12. 13. 14. References 1. 2. 3. 4. 5. 6. 7. 8. Crawford ED. Early versus late hormonal therapy: debating the issues. Urology. 2003;61:8–13. Crawford ED, Blumenstein BA. Proposed substages for metastatic prostate cancer. Urology. 1997;50:1027–1028. Pound CR, Partin AP, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:1591–1597. Bolla M, Collette L, Blank L, et al. 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A phase II study of docetaxel (Taxotere), estramustine, and low-dose hydrocortisone in men with hormonerefractory prostate cancer. J Clin Oncol. 2001; 19:2509–2516. VOL. 5 SUPPL. 6 2003 REVIEWS IN UROLOGY S53