Prostatic Neoplasms: Goldenberg SL

Thompson I, Thrasher JB, Aus G, Burnett AL, Canby-Hagino ED, Cookson MS, D'Amico AV, Dmochowski RR, Eton DT, Forman JD, Goldenberg SL, Hernandez J, Higano CS, Kraus SR, Moul JW, Tangen CM, Anonymous00324. · American Urological Association Education and Research, Inc. · J Urol. · Pubmed #17509297 No free full text.

This publication has no abstract.

Burnett AL, Aus G, Canby-Hagino ED, Cookson MS, D'Amico AV, Dmochowski RR, Eton DT, Forman JD, Goldenberg SL, Hernandez J, Higano CS, Kraus S, Liebert M, Moul JW, Tangen C, Thrasher JB, Thompson I, Anonymous00008. · The Johns Hopkins Hospital, 600 North Wolfe St., Marburg 407, Baltimore, Maryland 21287-2411, USA. · J Urol. · Pubmed #17570435 No free full text.

Abstract: PURPOSE: In conjunction with the assignment to update the Guidelines for Management of Clinically Localized Prostate Cancer, the American Urological Association Prostate Cancer Guideline Update Panel performed a side analysis of the reporting of erectile function outcomes in this clinical context as published in the medical literature. MATERIALS AND METHODS: Four National Library of Medicine PubMed(R) Services literature searches targeting articles published from 1991 through early 2004 were done to derive outcome reporting (efficacy or side effects) for the treatment of clinical stage T1 or T2 N0M0 prostate cancer. A database was constructed containing descriptions relating to erectile function as well as numerical frequency rates of complete erectile dysfunction, and partial and intact erectile function for various treatments. A literature review was also done, consisting of a PubMed Services search of current measures and protocols used for assessing erectile function outcomes and a survey of consensus opinion sources on the management of male sexual dysfunctions. RESULTS: Based on inclusion criteria 436 articles were selected. Of these articles database extraction from 100 pertaining to radical prostatectomy garnered various characterizations of erectile function, including qualitative descriptions, generic terminology and rating systems. Database extraction from 31 articles, in which results for at least 50 patients were reported, yielded ranges of rates for complete erectile dysfunction, partial erectile function and intact erectile function that were 26% to 100%, 16% to 48% and 9% to 86% for radical prostatectomy, 8% to 85%, 21% to 47% and 36% to 63% for external beam radiation, and 14% to 61%, 21% and 18% for interstitial radiation, respectively. The literature review showed an evolution in standards for studying and reporting erectile function outcomes. CONCLUSIONS: Clinical studies reporting erectile function outcomes after localized prostate cancer treatment often demonstrate poorly interpretable and inconsistent manners of assessment as well as widely disparate rates of erectile dysfunction and erectile function. Future studies must apply scientifically rigorous methodology and standard outcomes measures to advance this field of study.

Shaw GL, Wilson P, Cuzick J, Prowse DM, Goldenberg SL, Spry NA, Oliver T. · St Bartholemew's Hospital, London, UK, and University of Western Australia, Perth, Australia. · BJU Int. · Pubmed #17346277 No free full text.

Abstract: OBJECTIVE: To review pooled phase II data to identify features of different regimens of intermittent hormone therapy (IHT), developed to reduce the morbidity of treating metastatic prostate cancer, and which carries a theoretical advantage of delaying the onset of androgen-independent prostate cancer, (AIPC) that are associated with success, highlighting features which require exploration with prospective trials to establish the best strategies for using this treatment. METHODS: Individual data were collated on 1446 patients with adequate information, from 10 phase II studies with >50 cases, identified through Pubmed. RESULTS: Univariate and multivariate Cox proportional hazard models were developed to predict treatment success with a high degree of statistical success. The prostate-specific antigen (PSA) nadir, the PSA threshold to restart treatment, and medication type and duration, were important predictors of outcome. CONCLUSIONS: The duration of biochemical remission after a period of HT is a durable early indicator of how rapidly AIPC and death will occur, and will make a useful endpoint in future trials to investigate the best ways to use IHT based on the important treatment cycling variables described above. Patients spent a mean of 39% of the time off treatment. The initial PSA level and PSA nadir allow the identification of patients with prostate cancer in whom it might be possible to avoid radical therapy.

Cookson MS, Aus G, Burnett AL, Canby-Hagino ED, D'Amico AV, Dmochowski RR, Eton DT, Forman JD, Goldenberg SL, Hernandez J, Higano CS, Kraus SR, Moul JW, Tangen C, Thrasher JB, Thompson I. · Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA. · J Urol. · Pubmed #17222629 No free full text.

Abstract: PURPOSE: The American Urological Association Prostate Guideline Update Panel was charged with updating the Guidelines for Clinically Localized Prostate Cancer. In assessing outcomes with treatment, it became apparent that a highly variable number of definitions exist with respect to biochemical recurrence. Herein, we review the variability in published definitions of biochemical recurrence and make recommendations directed toward improving this terminology by recommending a standard definition in patients treated with radical prostatectomy. MATERIALS AND METHODS: Four PubMed literature searches were performed between May 2001 and April, 2004 and covered articles published from 1991 through early 2004. The search terms included the MeSH major headings of prostate cancer and prostatic neoplasm. All potentially relevant articles were retrieved and a more detailed screen for relevance was performed. An article was considered relevant if it reported treatment outcomes of patients with clinical T1 or T2N0M0 prostate cancer. Data extractors recorded the definition of biochemical recurrence and definitions were then collapsed into categories representing the same criteria. The results of biochemical failure were subcategorized by initial treatment. RESULTS: Of 13,800 citations, a total of 436 articles were selected. Among these, a total of 145 articles contained 53 different definitions of biochemical recurrence for those treated with radical prostatectomy. Of these, the most common definition (35) was a prostate specific antigen of >0.2 ng/mL or a slight variation thereof. In addition, a total of 208 articles reported 99 different definitions of biochemical failure among those treated with radiation therapy. Of these, the American Society for Therapeutic Radiology and Oncology definition (70) and/or a variation thereof was the most commonly reported. In total, 166 different definitions of biochemical failure were identified. Following radical prostatectomy, the Panel recommends defining biochemical recurrence as an initial serum prostate specific antigen of > or =0.2 ng/mL, with a second confirmatory level of prostate specific antigen of >0.2 ng/mL. The Panel recommends the use of the American Society for Therapeutic Radiology and Oncology criteria for patients treated with radiation therapy and acknowledges that these criteria will soon be updated although not yet published. CONCLUSIONS: A high degree of variability in the definition of biochemical recurrence exists following treatment for localized prostate cancer. Strict definitions for biochemical recurrence are necessary to identify men at risk for disease progression and to allow meaningful comparisons among patients treated similarly. The Panel acknowledges the American Society for Therapeutic Radiology and Oncology criteria and future modifications thereof for those receiving radiation therapy and recommends the newly developed American Urological Association criteria for those treated with radical prostatectomy. The purpose for the establishment of this standard is for data reporting purposes and for comparison of similarly treated patients. It is not intended to represent a threshold value for which to initiate treatment. The Panel acknowledges that the clinical decision to initiate treatment will be dependent on multiple factors including patient and physician interaction rather than a specific prostate specific antigen threshold value.

Pether M, Goldenberg SL. · The Prostate Centre at VGH, Division of Urology, Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada. · BJU Int. · Pubmed #14764118 No free full text.

This publication has no abstract.

Hurtado-Coll A, Goldenberg SL, Gleave ME, Klotz L. · Division of Urology, Prostate Centre at Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada. · Urology. · Pubmed #12231049 No free full text.

Abstract: The role of androgen withdrawal is well established in the treatment of advanced prostate cancer. In metastatic cancer the response rate is 70% to 80%, with a median duration of progression-free survival of 12 to 33 months and a median duration of overall survival of 23 to 37 months. There are limitations to the continuous use of androgen withdrawal therapy, including significant adverse effects with long-term use. More significantly, the cell death process induced by androgen ablation fails to eliminate the entire malignant cell population; recurrent tumors are characterized by androgen-independent growth. The concept of intermittent androgen suppression proposes that the maintenance of apoptotic potential by successive rounds of androgen withdrawal and replacement might forestall tumor progression. Intermittent therapy offers quality-of-life benefits during the off-therapy period, as well as reduced cost of treatment. This article will review the >15 years of Canadian experience with intermittent androgen suppression.

Hurtado-coll A, Goldenberg SL, Klotz L, Gleave ME. · Division of Urology, Prostate Centre at Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada. · Urology. · Pubmed #12231047 No free full text.

Abstract: The goal of radical prostatectomy is the complete removal of all cancer cells--no more, no less. Unfortunately, this is not always possible, especially in men with higher risk pathologic features. It is recognized that preoperative staging underestimates the extent of disease in < or =66% of cases, and that positive margin rates may be as high as 30% to 60%. Over the past 7 years in Canada, researchers have been investigating therapies that optimize the complete extirpation of all cancer cells with a minimum of morbidity and mortality. An example of this therapy is the combined modality approach of shrinking the prostate and tumor with androgen withdrawal therapy before surgical removal. The availability of potent, reversible, and well-tolerated forms of medical castration, and the sensitivity of serum prostate-specific antigen as a marker of response to therapy, makes neoadjuvant hormone therapy before localized therapy possible and appealing. In this article, we will review the Canadian experience, from the laboratory to the clinic.

Nasr R, Goldenberg SL. · Division of Urology, The Prostate Centre at Vancouver General Hospital, University of British Columbia,Vancouver, B.C, Canada. · Can J Urol. · Pubmed #11564273 No free full text.

Abstract: Prostate specific antigen (PSA) has been proven to be a valuable tool in the diagnosis and staging of early prostate cancer and as a sensitive marker of residual or recurrent cancer after curative therapy. In 1998, 200 000 new cases of prostate cancer were reported in the SEER database. Two-thirds of these, or 134 000 men, underwent definitive therapy for localized cancer, including approximately 75 000 radical prostatectomies. It has been reported that 20%-50% of radical prostatectomy patients will have a PSA only recurrence. One can therefore estimate that every year 15 000 to 38 000 men will have a rising PSA following definitive surgical therapy. This elevation of PSA often precedes clinical failure by many years and poses a difficult management problem for which there are not, as yet, definitive management guidelines. This paper will review the definition of PSA recurrence, the natural history, diagnostic options and the therapeutic choices, as illustrated by several genuine cases.

Klotz L, Gleave M, Goldenberg SL. · Sunnybrook Health Science Center, University of Toronto, Toronto, Ontario, Canada. · Mol Urol. · Pubmed #11062379 No free full text.

Abstract: The Canadian Urologic Oncology Group has carried out three studies of neoadjuvant hormonal therapy (NHT) in prostate cancer. The first, a study of 3 months of cyproterone acetate (CPA) 100 mg TID in patients undergoing external-beam radiation therapy, showed a benefit with respect to time to biochemical progression. There are no survival or clinical progression data available from this study. The second study involved 3 months of CPA prior to radical prostatectomy compared with radical prostatectomy alone and enrolled 200 patients. The probability of biochemical progression at 36 months was similar in the two groups (CPA 40%; surgery alone 30%; P = 0.3233). More recently, we have carried out a randomized trial of 3 v 8 months of leuprolide plus flutamide prior to radical prostatectomy in 547 patients. Patients were stratified by clinical stage, Gleason grade, and serum prostate specific antigen (PSA) concentration. In the 3- and 8-month groups, presurgery PSA concentrations were <0.1 ng/mL in 35% v 73%, and >0.3 ng/mL in 37% v 10%, respectively. In the 3- and 8-month groups, the positive margin rates were 17% and 5% and the organ-confined rates 71% and 91% (P < 0.01). One-year follow-up is now available on the entire cohort. Data regarding time to biochemical and clinical progression and overall and disease-specific survival will be required to determine whether this change in the pathologic findings translates into a patient benefit.

Bruchovsky N, Klotz L, Crook J, Phillips N, Abersbach J, Goldenberg SL. · The Prostate Centre at Vancouver General Hospital, Department of Urologic Sciences, University of British Columbia, Canada. · Clin Genitourin Cancer. · Pubmed #18501083 No free full text.

Abstract: BACKGROUND: Observations of quality of life (QOL), morbidity, and mortality were obtained from the results of a prospective phase II study of intermittent androgen suppression for recurrent prostate cancer after radiation therapy. PATIENTS AND METHODS: Patients with histologically confirmed adenocarcinoma of the prostate and a rising serum prostate-specific antigen level after external-beam radiation of the prostate were treated intermittently with a 36-week course of cyproterone and leuprolide. At predetermined intervals, QOL was assessed using the Southwest Oncology Group 9346 QOL and the American Urological Association symptom score questionnaires. Progression-free and overall survival rates were estimated using the Kaplan-Meier method. Parameters related to progression were explored with univariate and multivariate analyses. RESULTS: The incidence of adverse events was higher when patients were on treatment. Fatigue, dyspnea, and hematuria were the most common symptoms and signs recorded (50.5%, 24.8%, and 17.4%, respectively). Less frequent were myocardial infarction (7.3%), cerebrovascular accident (6.4%), and deep vein thrombosis (5.5%). Quality of life improved when off treatment, as indicated by a shift toward baseline levels in the scales depicting physical and work functions, hot flashes, impotence, sexual performance, urgency, and nocturia. Biochemical recurrence-free survival at 5 years was 70%, with a median > 6 years. The overall 5-year survival was 80%, similar to that of an age-matched population of normal men. CONCLUSION: Intermittent androgen suppression is a potentially useful treatment for locally recurrent prostate cancer after radiation therapy with QOL benefits in the off-treatment interval and no apparent deleterious effects on short- to medium-term survival.

Bruchovsky N, Klotz L, Crook J, Goldenberg SL. · The Prostate Center at Vancouver General Hospital, Division of Urology, Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada. · Cancer. · Pubmed #17265527 links to  free full text

Abstract: BACKGROUND: Biochemical results from a prospective Phase II trial of intermittent androgen suppression for recurrent prostate cancer after radiotherapy were analyzed for correlations to the onset of hormone-refractory disease. METHODS: Patients with histologically confirmed adenocarcinoma of the prostate and a rising serum prostate-specific antigen (PSA) level after external beam irradiation of the prostate were treated intermittently with a 36-week course of cyproterone acetate and leuprolide acetate. Then, patients were stratified according to their serum PSA range at the start of each cycle and were followed with further biochemical testing until disease progression was evident. RESULTS: The mean PSA reduction was 95.2% irrespective of stratification group. A baseline serum PSA level <10 microg/L and a serum PSA nadir <or=0.2 microg/L were associated with the longest time off treatment. The overall mean nadir PSA value in the progression group at 1.40 +/- 0.19 microg/L was 2.6-fold greater than the value of 0.55 +/- 0.88 microg/L in the no-progression group (P = .0002). Recovery of serum testosterone to a level of >or=7.5 nmol/L was observed in 75%, 50%, 40%, and 30% of men in Cycles 1 to 4, respectively, and was sufficient to normalize the level of hemoglobin in each cycle, which dropped by an average of 10.8 g/L during treatment (P < .0001). CONCLUSIONS: The length of the off-treatment interval during cyclic androgen withdrawal therapy was related inversely to baseline and nadir levels of serum PSA. Nadir PSA was a powerful predictor of early progression to androgen independence.

Bruchovsky N, Klotz L, Crook J, Malone S, Ludgate C, Morris WJ, Gleave ME, Goldenberg SL. · The Prostate Center at Vancouver General Hospital, Division of Urology, Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada. · Cancer. · Pubmed #16783817 links to  free full text

Abstract: BACKGROUND: This prospective Phase II study was undertaken to evaluate intermittent androgen suppression as a form of therapy in men with localized prostate cancer who failed after they received external beam irradiation. METHODS: Patients who demonstrated a rising serum prostate-specific antigen (PSA) level after they received radiotherapy and who were without evidence of distant metastasis were accepted into the study. Treatment in each cycle consisted of cyproterone acetate given as lead-in therapy for 4 weeks, followed by a combination of leuprolide acetate and cyproterone acetate, which ended after a total of 36 weeks. RESULTS: Of 109 patients registered, 103 patients were eligible for interruption of treatment, yielding a PSA response rate of 95%. The study continued for 6 years with a mean follow-up of 3.7 years (median follow-up, 4.2 years). The time off treatment averaged 53% of the total cycle time but, in absolute terms, decreased with each succeeding cycle, ranging from 63.7 weeks in Cycle 1 to 25.6 weeks in Cycle 5. Prostate volume was reduced by 40% in Cycle 1 and by 34% in Cycle 2, and there were no decreases in Cycle 3 or Cycle 4. At the end of the trial, 38.5% of patients still were receiving treatment, 23.9% of patients had failed, and 15.6% of patients had died. Only 2% of deaths were cancer-specific. CONCLUSIONS: Biochemical recurrence after irradiation for localized prostate cancer was amenable to cyclic androgen withdrawal therapy and showed a high response rate. Despite progressively shorter treatment cycles, the off-treatment interval remained appreciable, ranging from 65% in Cycle 1 to 46% in Cycle 5.

Chi KN, Eisenhauer E, Fazli L, Jones EC, Goldenberg SL, Powers J, Tu D, Gleave ME. · Vancouver Cancer Centre, BC Cancer Agency, Vancouver, British Columbia, V5Z 4E6, Canada. · J Natl Cancer Inst. · Pubmed #16145049 links to  free full text

Abstract: BACKGROUND: Clusterin is a cytoprotective chaperone protein that promotes cell survival and confers broad-spectrum treatment resistance. OGX-011 is a 2'-methoxyethyl modified phosphorothioate antisense oligonucleotide that is complementary to clusterin mRNA and has been reported to inhibit clusterin expression and enhance drug efficacy in xenograft models. The primary objective of this clinical study was to determine a biologically effective dose of OGX-011 that would inhibit clusterin expression in human cancer. METHODS: Subjects (n = 25) with localized prostate cancer with high-risk features who were candidates for prostatectomy were treated with OGX-011 by 2-hour intravenous infusion on days 1, 3, and 5 and then weekly from days 8-29 combined with androgen blockade starting on day 1; prostatectomy was performed on days 30-36. Six different doses were tested, from 40 to 640 mg. OGX-011 plasma and prostate tissue concentrations were measured by an enzyme-linked immunosorbent assay method, and the pharmacokinetics of OGX-011 were determined from these data. Prostate cancer tissue, lymph nodes, and serial samples of peripheral blood mononuclear cells were assessed for clusterin expression using quantitative real-time polymerase chain reaction and immunohistochemistry. All statistical tests were two-sided. RESULTS: Only grade 1 and 2 toxicities were observed. The plasma half-life of OGX-011 was approximately 2-3 hours, and the area under the concentration versus time curve and CMAX (peak plasma concentration) increased proportionally with dose (Ptrend < .001). OGX-011 in prostate tissue increased with dose (Ptrend < .001). Dose-dependent decreases in prostate cancer and lymph node clusterin expression were observed by polymerase chain reaction of greater than 90% (Ptrend = .008 and Ptrend < .001, respectively) and by immunohistochemistry (Ptrend < .001 and Ptrend = .01, respectively). CONCLUSIONS: OGX-011 is well tolerated and reduces clusterin expression in primary prostate tumors. The optimal biologic dose for OGX-011 at the schedule used is 640 mg.

Klotz LH, Goldenberg SL, Jewett MA, Fradet Y, Nam R, Barkin J, Chin J, Chatterjee S, Anonymous00398. · Division of Urology, Sunnybrook and Women's College Health Sciences Centre MG408, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. · J Urol. · Pubmed #12913699 No free full text.

Abstract: PURPOSE: In 1992 we initiated a national randomized prospective trial of 3 months of cyproterone acetate before radical prostatectomy compared to prostatectomy alone. Initial results indicated a 50% decrease in the rate of positive surgical margins. This decrease did not translate into a difference in prostate specific antigen (PSA) progression at 3 years. This report is on the long-term outcome (median followup 6 years) of this cohort. MATERIALS AND METHODS: This prospective, randomized, open label trial compared 100 mg cyproterone acetate 3 times daily for 3 months before surgery to surgery alone. Randomization occurred between January 1993 and April 1994. Patients were stratified according to clinical stage, baseline serum PSA and Gleason sum. A total of 213 patients were accrued. Biochemical progression was defined as 2 consecutive detectable PSAs (greater than 0.2 ng/ml) at least 4 weeks apart, re-treatment or death from prostate cancer. RESULTS: A total of 34 (33.6%) patients undergoing surgery only and 42 (37.5%) patients given neoadjuvant hormone therapy (NHT) had biochemical recurrence during the median followup of 6 years. Despite the significant pathological down staging in this study, there was no significant difference in number of patients with no evidence of biochemical disease (bNED) survival (p = 0.732). A bNED survival benefit favoring NHT was seen in men with a baseline PSA greater than 20 (p = 0.015). CONCLUSIONS: After 6 years of followup there was no overall benefit with 3 months of NHT. Improved bNED survival was seen in the highest risk PSA group (PSA greater than 20). The possibility that high risk patients may benefit from NHT warrants further investigation.

Bullock MJ, Srigley JR, Klotz LH, Goldenberg SL. · Q.E. II Health Science Center and Dalhousie University, Halifax, Nova Scotia. · Am J Surg Pathol. · Pubmed #12409716 No free full text.

Abstract: Neoadjuvant hormonal therapy (NHT; androgen ablation) is used prior to radical prostatectomy (RP) in an attempt to pathologically "downstage" prostatic adenocarcinoma and ultimately to improve disease-free survival. This study describes the pathologic effects of NHT with the antiandrogen cyproterone acetate, 300 mg/day for 12 weeks, on the RP specimens from men with clinically localized (stage T1 or T2) prostatic adenocarcinoma. There were 101 men in the pretreatment group (CPA) and 91 men in a control group who were treated with surgery alone. The prevalence and extent of morphologic effects were recorded for the nonneoplastic prostate, high-grade prostatic intraepithelial neoplasia, and invasive adenocarcinoma. The commonest effects on the nonneoplastic prostate were atrophy and basal cell hyperplasia and prominence. High-grade prostatic intraepithelial neoplasia was more commonly identified in the surgery alone group than the CPA group (p <0.01). In the CPA group, flat and low tufted patterns of high-grade prostatic intraepithelial neoplasia predominated. Following NHT, the adenocarcinoma showed characteristic morphologic alterations, including reduction in cytoplasmic quantity, cytoplasmic vacuolation, nuclear pyknosis, reduced gland diameter, and mucinous breakdown. In many cases there was prominence of collagenous stroma, obscuring malignant glands. Compared with the surgery alone group, the CPA group RP specimens had a significantly lower mean specimen weight (40.3 g vs 46.5 g, p = 0.025) and less tumor extent by several measures. Organ-confined tumor (stage pT2, margin negative) was found in 41.6% of the CPA group compared with 19.8% of the surgery alone group (p = 0.0017). The overall rate of margin positivity was lower in the CPA group (27.7% vs 64.8%, p = 0.001). We consider that the difference in margin positivity is the result of tumor shrinkage with a decreased likelihood of sampling in routine sections. There was no significant difference in the rate of extraprostatic extension between the two groups. There was elevation of the Gleason score in the RP specimens versus baseline biopsy in 60% of the CPA group compared with 33% of the surgery alone group (p = 0.02). The higher rate of elevation in the CPA group largely resulted from an increase in primary or secondary Gleason score 5 tumor, a morphologic artifact introduced by NHT. Because of this, we recommend not giving a Gleason grade to RP specimens following NHT. Monotherapy with CPA has similar pathologic effects on benign and malignant prostate tissue as does dual agent androgen blockade. Prolonged follow-up of these patients is required to determine if NHT with CPA leads to improved disease-free survival.

Gleave ME, Goldenberg SL, Chin JL, Warner J, Saad F, Klotz LH, Jewett M, Kassabian V, Chetner M, Dupont C, Van Rensselaer S, Anonymous00203. · Vancouver Hospital and Health Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada. · J Urol. · Pubmed #11458055 No free full text.

Abstract: PURPOSE: A prospective phase 3 trial was initiated to determine whether 8 compared with 3-month neoadjuvant hormonal therapy reduces prostate specific antigen (PSA) recurrence rates after radical prostatectomy. Our interim analysis includes secondary end points of differences in biochemistry, pathology and adverse events between the 2 groups. MATERIALS AND METHODS: Men with clinically confined prostate cancer were randomized to receive 7.5 mg. leuprolide intramuscularly monthly and 250 mg. flutamide orally 3 times daily for 3 or 8 months before radical prostatectomy. Our study was powered to detect a 35% decrease in PSA recurrence, assuming a 30% recurrence rate in the 3-month arm after 3 years. RESULTS: A total of 547 men were randomized between August 1995 and April 1998. Men in the 8 and 3-month groups were equally stratified for T stage (29% T1c, 70% T2), Gleason grade (68% less than 4, 32% 4 or greater) and pretreatment PSA (63% less than 10, 27% 10 to 20 and 10% greater than 20 microg./l.). Mean pretreatment PSA was slightly higher in the 8-month compared with the 3-month group (11.64 versus 9.95 microg./l., respectively, p = 0.0539). A total of 44 men withdrew from study before surgery and, therefore, were nonevaluable. Preoperative PSA nadir was less than 0.1 microg./l. in 43.3% versus 75.1% (p <0.0001), and 0.3 microg./l. or greater in 21% versus 9.2% after 3 versus 8 months, respectively (p <0.0006). Mean serum PSA decreased 98% to 0.12 microg./l. after 3 months, with a further 57% to 0.052 microg./l. from 3 to 8 months. Transrectal ultrasound determined that prostatic volume decreased 37% from a mean of 40.6 to 25.4 cc after 3-month neoadjuvant hormonal therapy (p = 0.0001) and a further 13% to 22.2 cc after 8 months (p = 0.03). Mean hemoglobin decreased 15% (148.2 to 125.4 gm./dl.) after 3-month neoadjuvant hormonal therapy but stabilized thereafter. Radical prostatectomy was completed in 500 men, while surgery was aborted intraoperatively in 3. Positive margin rates were significantly lower in the 8 than 3-month group (12% versus 23%, respectively, p = 0.0106). There were no fatal adverse events and no differences between the 2 groups in the severity or causality (p = 0.287, 0.0564) of adverse events, or incidence of increased liver enzymes or diarrhea (p = 0.691, 0.288, respectively). However, men in the 8-month group noticed a higher number of newly reported adverse events (4.5 versus 2.9, p <0.0001) and higher incidence of hot flushes than the 3-month group (87% versus 72%, respectively, p <0.0001). CONCLUSIONS: Ongoing biochemical and pathological regression of prostate tumors occurs between 3 and 8 months of neoadjuvant hormonal therapy, suggesting that the optimal duration of neoadjuvant hormonal therapy is longer than 3 months. Longer followup is needed to determine whether longer therapy alters PSA recurrence rates.

Bruchovsky N, Klotz LH, Sadar M, Crook JM, Hoffart D, Godwin L, Warkentin M, Gleave ME, Goldenberg SL. · Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Mol Urol. · Pubmed #11062374 No free full text.

Abstract: The Canadian Prospective Trial of intermittent androgen suppression was a prototype therapeutic initiative started in 1995 for the management of patients in biochemical relapse after radiation for localized prostate cancer. An interim analysis has yielded several observations on the relations between baseline serum prostate specific antigen (PSA), nadir serum PSA, Gleason score, and time off-treatment. In a typical androgen-dependent tumor, the response of serum PSA to androgen withdrawal is biphasic, but with early tumor progression, plateauing of serum PSA is observed. Ligand-independent activation of the androgen receptor, a mechanism subserving the initiation of androgen independence, can be counteracted experimentally with decoy molecules and clinically with nonsteroidal antiandrogens. In some patients, it is possible to lengthen the off-treatment interval by inhibiting the enzyme 5 alpha-reductase, an effect that can be reinforced by lowering serum testosterone with an antigonadotropin. Serial measurements of serum PSA indicate that intermittent androgen suppression engenders a more diverse range of hormone-related responses than previously appreciated. These include: (1) repeated differentiation of tumor with recovery of apoptotic potential; (2) inhibition of tumor growth by rapid restoration of serum testosterone; and (3) restraint of tumor growth by subnormal levels of serum testosterone. These responses are aspects of regulation that should be taken into account when planning long-term treatment of prostate cancer with intermittent androgen suppression.

Klotz LH, Goldenberg SL, Jewett M, Barkin J, Chetner M, Fradet Y, Chin J, Laplante S. · Department of Surgery, University of Toronto Sunnybrook Health Science Centre, Ontario, Canada. · Urology. · Pubmed #10197852 No free full text.

Abstract: OBJECTIVES: To test the hypothesis that neoadjuvant androgen ablation before radical prostatectomy reduces the likelihood of biochemical progression at 36 months. METHODS: Two hundred thirteen patients with localized prostate cancer were randomized to radical prostatectomy alone (Sx, n = 101) or a 12-week course of 300 mg of cyproterone acetate daily followed by surgery (CPA, n = 112). Biochemical progression (two consecutive detectable prostate-specific antigen [PSA] values) was determined for the entire group and by baseline PSA, Gleason score, clinical stage, and pathologic stage. RESULTS: The probability of biochemical progression at 36 months was similar in both groups (CPA 40.2%, Sx 30.1%; P = 0.3233). CPA patients with baseline serum PSA between 25 and 50 ng/mL had a lower probability of biochemical progression (CPA 63.5%, Sx 84.6%; P = 0.0038). No difference in the probability of biochemical progression was seen between groups when analyzed by clinical stage or Gleason score. When analyzed by pathologic margin status, no difference was observed in the probability of biochemical progression in patients with organ-confined disease (P = 0.4484). There was a trend for a higher probability of progression in the neoadjuvant arm in patients with positive and negative surgical margins (P = 0.0105, P = 0.0459; alpha = 0.005 with Bonferroni adjustment). CONCLUSIONS: Neoadjuvant androgen ablation with CPA reduces the positive margin rate significantly but does not result in a difference in biochemical progression at 3 years. This may be due to a lack of sufficient follow-up, insufficient power of the trial to demonstrate a small benefit, or a true lack of benefit of neoadjuvant androgen ablation before radical prostatectomy.

Davison BJ, So A, Goldenberg SL, Berkowitz J, Gleave ME. · Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. · BJU Int. · Pubmed #18005198 No free full text.

Abstract: OBJECTIVE: To identify factors that patients with prostate cancer believe to be important determinants in their decisions about future enrolment in clinical trials. PATIENTS AND METHODS: In all, 122 patients (within 5 years of a diagnosis of prostate cancer) who had never been asked to participate in a clinical trial were asked to complete a 30-item measure of 'Factors Influencing Participation' in clinical trials. RESULTS: Factor analysis showed that variables influencing participation can be grouped into three areas: acceptability (e.g. recruitment process and altruistic beliefs); awareness (e.g. impact on quality of life, survivorship and randomization process); and accessibility (e.g. costs to patient, influence of family, age, time and need for extra tests). Awareness items were rated significantly more important by patients with T1 or T2 disease (P = 0.002). Patients who had not made a treatment decision also rated awareness (P = 0.05) and acceptability (P = 0.04) items higher. Patients with less than a university education identified access items as more important (P = 0.03). Helping future patients with prostate cancer, the impact of the study protocol on survival, being fully informed about the study, relationship with specialists, and impact of study on quality of life were identified as the five variables having the most influence on future enrolment. CONCLUSIONS: Men rated items related to awareness and acceptability as being the most important determinants to future enrolment in a clinical trial. Knowledge about what these men believe is important for their future participation in a clinical trial will help researchers to design protocols that address the needs of targeted patient groups.

Davison BJ, Goldenberg SL, Wiens KP, Gleave ME. · Prostate Centre at Vancouver General Hospital, Vancouver, British Columbia, Canada. · Cancer Nurs. · Pubmed #17876177 No free full text.

Abstract: A randomized study was conducted to compare a generic and individualized approach to providing decisional support to men newly diagnosed with localized prostate cancer. Patients (N = 324) were referred by community urologists to a patient education center where they were randomly assigned to receive either an individualized or generic information intervention. Men assigned to the generic group viewed a video on the various treatments available for localized prostate cancer. Men in the individualized information group used a computer program to identify their information preferences. Computer printouts on top information preferences were individualized according to patient's specific disease characteristics, followed by a discussion of the pros and cons of each recommended treatment option. Both groups received a standardized package of written information. Men completed measures of decision control, satisfaction, and decision conflict at baseline and after a definitive treatment decision was made. Results demonstrated that overall both groups reported increased levels of decision control and lower levels of decision conflict after their treatment decision. All men reported being satisfied with their preparation to make a treatment decision. Compared to the generic information group, men who received the individualized information were more satisfied with the type, amount and method of providing information, and role played in treatment decision making with their physician (P < .002). Both information interventions seem to be similar in providing decisional support to this group of men at the time of diagnosis. Further research is required to determine how to identify men who may benefit from a more individualized approach.

Davison BJ, So AI, Goldenberg SL. · Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. · BJU Int. · Pubmed #17578466 No free full text.

Abstract: OBJECTIVE: To examine the effect of changes in quality of life (QoL) and levels of sexual function on decisional regret after surgical treatment of localized prostate cancer. PATIENTS AND METHODS: Patients who decided to have a radical prostatectomy (RP) were assessed for health-related QoL using the general European Organization for Research and Treatment of Cancer C30 instrument and disease-specific prostate cancer module, and sexual function using the abbreviated International Index of Erectile Function-5 before and 1 year after RP. Decision control was measured before RP, and decisional regret 1 year afterward, using measures mailed to participants 1 year after treatment. RESULTS: Of 130 respondents (mean age 62 years), 4% expressed regret over their decision to have surgery. Physical and social functioning, and finances, were compromised, while emotional functioning and treatment-related symptoms improved by 1 year. Higher levels of decisional regret were correlated with decreases in role and social functioning, increased pain and financial difficulty (all P < 0.01). Sexual function was decreased (P < 0.001) after treatment. Men reported feeling less masculine, having less sexual enjoyment, difficulty in getting and maintaining an erection, and discomfort when being sexually intimate after surgery. Mean scores of decisional regret were similar among patients who reported assuming either active (84%) or collaborative (11%) roles in treatment decision-making. Men who assumed a passive role reported the most variability and highest scores on decision regret. CONCLUSIONS: Few men regretted having RP at 1 year after treatment, even though some QoL functions and domains were significantly affected. Ongoing assessment of the effect of surgical treatment on sexual function, sexuality and masculinity certainly deserves further exploration with this group of cancer survivors.

Kozlowski P, Chang SD, Goldenberg SL. · Prostate Centre at Vancouver General Hospital, Vancouver, British Columbia, Canada V6H 3Z6. · Magn Reson Imaging. · Pubmed #17566687 No free full text.

Abstract: Diffusion-weighted (DW) MRI at 1.5 T was carried out in two groups of patients. MRI data were correlated with the biopsy and histopathology (where available). The performance of two sequences -- a single-shot FSE (14 patients) and a single-shot EPI (15 patients) -- was compared. Average ADC values from the normal peripheral zone (PZ), central gland (CG) and the tumour [prostate carcinoma (PCa)] were calculated from b values of 0 and 600. Tukey-Kramer test was used for statistical analysis. EPI produced higher values of ADC (10(-3) mm(2)/s) than FSE sequence: 1.992+/-0.208 vs. 1.573+/-0.270 in PZ (P<.001), 1.518+/-0.126 vs. 1.373+/-0.179 in CG and 1.214+/-0.254 vs. 0.993+/-0.158 in PCa (P<.01). In conclusion, both EPI and FSE sequences showed differences in ADC between normal PZ, CG and PCa; however, EPI produced significantly higher ADC values than FSE.

Kozlowski P, Chang SD, Jones EC, Berean KW, Chen H, Goldenberg SL. · Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada. · J Magn Reson Imaging. · Pubmed #16767709 No free full text.

Abstract: PURPOSE: To determine whether the combination of diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI provides higher diagnostic sensitivity for prostate cancer than each technique alone. MATERIALS AND METHODS: Fourteen patients with a clinical suspicion of prostate cancer underwent endorectal MRI on a 1.5T scanner prior to transrectal ultrasound (TRUS)-guided biopsies. The average values of the apparent diffusion coefficient (ADC, calculated from b-values of 0 and 600), K(trans), v(e), maximum gadolinium (Gd) concentration, onset time, mean gradient, and maximum enhancement were determined. Correlation with histology was based on biopsy (six patients) and prostatectomy specimen (eight patients) results. The Tukey-Kramer test was used for statistical analysis. RESULTS: The average values of all MRI parameters, except v(e) and maximum Gd concentration, showed significant differences between tumor and normal prostate. The sensitivity and specificity values were respectively 54% (35-72%) and 100% (95-100%) for the ADC data, and 59% (39-77%) and 74% (63-83%) for the DCE data. When both ADC and DCE results were combined, the sensitivity increased to 87% (68-95%) and specificity decreased to 74% (62-83%). CONCLUSION: All but two DW- and DCE-MRI parameters showed significant differences between tumor and normal prostate. Combining both techniques provides better sensitivity, with a small decrease in specificity.

Davison BJ, Keyes M, Elliott S, Berkowitz J, Goldenberg SL. · Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada. · BJU Int. · Pubmed #15142144 No free full text.

Abstract: OBJECTIVE: To identify the preferences for sexual information resources of patients before and after definitive treatment for early-stage prostate cancer with either radical prostatectomy (RP) or brachytherapy. PATIENTS AND METHODS: Two hundred patients (mean age 64 years) treated with either RP or brachytherapy were recruited from radiation oncology (100) and urology (100) outpatient clinics. Patients completed a survey questionnaire to identify the types of information used, preferred sources of information, knowledge of treatments for erectile dysfunction (ED), effect of sexual function on the treatment decision, and the International Index of Erectile Function (IIEF) to assess their current level of sexual function. RESULTS: Urologists were identified as the main source of sexual information. Written information, Internet access and videos were identified as preferred sources of information before and after treatment. The effects of treatment on sexual function had no apparent significant influence on the men's definitive treatment choice. Compared with patients in the brachytherapy group, patients in the RP group reported having significantly higher levels of sexual desire (P < 0.001) after treatment, but otherwise the erectile domains of the groups were remarkably similar. Two-thirds of patients wanted more information on the effects of treatment on sexual function, and on available treatments for ED. CONCLUSIONS: These results support the need for physicians to offer patients access to information on the effect of treatment for early-stage prostate cancer on erectile function before and after treatment.

Davison BJ, Parker PA, Goldenberg SL. · Prostate Centre at Vancouver General Hospital, Vancouver, British Columbia, Canada. · BJU Int. · Pubmed #14678366 No free full text.

Abstract: OBJECTIVES: To assess patients' preferences about how physicians' deliver news of a prostate cancer diagnosis, and patients' preferred participation in medical decision-making, with a secondary objective being to validate the Measure of Patients' Preferences (MPP) scale with these patients. PATIENTS AND METHODS: Eighty-seven men (mean age 62.4 years) referred to an ultrasound/radiology department for their first transrectal ultrasonography (TRUS)-guided biopsy completed the MPP and Control Preferences measures. Patients were asked to identify how they would like to be told about a potential prostate cancer diagnosis by their physician, and what role they would like in making treatment-related decisions with their physicians. RESULTS: Most patients wanted either an active (43%) or collaborative (47%) role in medical decision-making if the TRUS showed prostate cancer. Men rated content items (what and how much information is provided by their physician) as more important than supportive (emotional support during interaction) or facilitative (setting and context variables) items. Men who preferred a collaborative role in the patient-physician interaction wanted significantly (P = 0.04) more content (detailed information on available treatments and the effect of these treatments on their quality of life) than men who had a preference for either an active or passive role in medical decision-making. Demographic characteristics were not indicative of either preferred role in decision-making or communication preferences. The MPP was shown to be reliable. CONCLUSIONS: Men have expectations about how physicians disclose a diagnosis of prostate cancer and how they wish to participate in making treatment decisions. These results underline the importance of identifying patient preferences before embarking on treatment discussions, as the way 'bad news' is disclosed has previously been identified as a predictor of the outcome of the patient-physician interview.