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Purpose: Neoadjuvant radiation therapy (RT) improves disease control in various cancers and has become an established oncologic treatment strategy. During 2001 to 2004, we conducted a phase 1 pilot study assessing the role of short-course preoperative RT (PreORT) for men with unfavorable intermediate- and high-risk localized prostate cancer. Herein, we present long-term follow-up toxicity and oncologic outcomes., Methods and Materials: Eligible patients had histologically proven prostate cancer, cT1-T2N0M0 disease, prostate-specific antigen >15 to 35 ng/mL regardless of Gleason score, or prostate-specific antigen 10 to 15 ng/mL with Gleason score ≥7. Patients received 25 Gy in 5 consecutive daily fractions (5 Gy per fraction) to the prostate only, followed by radical prostatectomy within 14 days after RT completion. Primary outcomes were intraoperative morbidity and late genitourinary (GU) and gastrointestinal toxicities., Results: In total, 15 patients were enrolled; 14 patients completed PreORT followed by radical prostatectomy, which also included bilateral lymph node dissections in 13 cases. Median follow-up was 12.2 years (range, 6.7-16.3). Late GU toxicity was common, with 2 patients (13.3%) experiencing G2 toxicity and 6 patients (40%) G3 toxicity. There were no patients with G4 to G5 late GU toxicity. Late gastrointestinal toxicity was infrequent, with only 1 patient (6.7%) experiencing transient G2 proctitis. At last follow-up, 8 (53.3%) and 6 (40%) patients experienced biochemical and metastatic disease recurrence, respectively., Conclusions: The use of PreORT in men with high-risk prostate cancer is associated with unexpected high rates of late GU toxicity. Future studies examining the role of RT preradical prostatectomy must cautiously select RT technique and dose schedule. Importantly, long-term follow-up data are essential to fully determine the therapeutic index of PreORT in the management of localized disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The most prevalent intervention for localized prostate cancer (pca) is radical prostatectomy (rp), which has a 10-year relative survival rate of more than 90%. The improved survival rate has led to a focus on reducing the burden of treatment-related morbidity and improving the patient and partner survivorship experience. Post-rp sexual dysfunction (sdf) has received significant attention, given its substantial effect on patient and partner health-related quality of life. Accordingly, there is a need for sdf treatment to be a fundamental component of pca survivorship programming., Methods: Most research about the treatment of post-rp sdf involves biomedical interventions for erectile dysfunction (ed). Although findings support the effectiveness of pro-erectile agents and devices, most patients discontinue use of such aids within 1 year after their rp. Because side effects of pro-erectile treatment have proved to be inadequate in explaining the gap between efficacy and ongoing use, current research focuses on a biopsychosocial perspective of ed. Unfortunately, there is a dearth of literature describing the components of a biopsychosocial program designed for the post-rp population and their partners., Results: In this paper, we detail the development of the Prostate Cancer Rehabilitation Clinic (pcrc), which emphasizes multidisciplinary intervention teams, active participation by the partner, and a broad-spectrum medical, psychological, and interpersonal approach., Conclusions: The goal of the pcrc is to help patients and their partners achieve optimal sexual health and couple intimacy after rp, and to help design cost-effective and beneficial rehabilitation programs., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

Purpose: The American College of Surgeons Oncology Group phase III Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial comparing radical prostatectomy (RP) and brachytherapy (BT) closed after 2 years due to poor accrual. We report health-related quality of life (HRQOL) at a mean of 5.3 years for 168 trial-eligible men who either chose or were randomly assigned to RP or BT following a multidisciplinary educational session., Patients and Methods: After initial lack of accrual, a multidisciplinary educational session was introduced for eligible patients. In all, 263 men attended 47 sessions. Of those, 34 consented to random assignment, 62 chose RP, and 94 chose BT. Five years later, these 190 men underwent HRQOL evaluation by using the cancer-specific 50-item Expanded Prostate Cancer Index Composite, the Short Form 12 Physical Component Score, and Short Form 12 Mental Component Score. Response rate was 88.4%. The Wilcoxon rank sum test was used to compare summary scores between the two interventions., Results: Of 168 survey responders, 60.7% had BT (9.5% randomly assigned) and 39.3% had RP (9.5% randomly assigned). Median age was 61.4 years for BT and 59.4 for RP (P = .05). Median follow-up was 5.2 years (range, 3.2 to 6.5 years). For BT versus RP, there was no difference in bowel or hormonal domains, but men treated with BT scored better in urinary (91.8 v 88.1; P = .02) and sexual (52.5 v 39.2; P = .001) domains, and in patient satisfaction (93.6 v 76.9; P < .001)., Conclusion: Although treatment allocation was random in only 19%, all patients received identical information in a multidisciplinary setting before selecting RP, BT, or random assignment. HRQOL evaluated 3.2 to 6.5 years after treatment showed an advantage for BT in urinary and sexual domains and in patient satisfaction.

Purpose: Positive surgical margins have a negative impact on disease outcomes after radical prostatectomy, yet their prognostic value may vary depending on specific pathological characteristics. We examined the relationship of positive surgical margins to biochemical progression according to several clinicopathological features., Materials and Methods: We analyzed data from 1,268 patients who underwent radical prostatectomy for clinically localized prostate cancer at our center between 1992 and 2008, and did not receive any neoadjuvant or adjuvant treatment. We examined the relation of age, pretreatment prostate specific antigen, pathological T stage, radical prostatectomy Gleason score, disease risk group and surgical margin status to biochemical progression-free survival., Results: The overall positive surgical margin rate was 20.8% and median followup was 79 months. The impact of positive surgical margins was dependent on risk group. Biochemical progression-free survival was 99.6% for the negative surgical margin group vs 94.9% for the positive surgical margin group in low risk disease (log rank p = 0.53), 93.5% for the negative surgical margin group vs 83% for the positive surgical margin group in intermediate risk disease (log rank p <0.001) and 78.5% for the negative surgical margin group vs 57.1% for the positive surgical margin group in high risk disease (log rank p = 0.003). These differences remained significant in a multivariate Cox regression model adjusting for other clinicopathological features., Conclusions: Positive surgical margins are an independent predictor of biochemical progression in patients with intermediate and high risk prostate cancer. Patients with low risk disease have a favorable long-term outcome regardless of margin status and may be candidates for expectant management even with positive surgical margins, sparing them the side effects and costs of treatment.

Purpose: Laparoscopic or robot assisted laparoscopic radical prostatectomy is often performed via a transperitoneal approach for prostate cancer, in contrast to open retropubic radical prostatectomy. Theoretically transgressing the peritoneum may introduce small bowel loops into the pelvis, increasing the risk of small bowel injury with adjuvant radiotherapy. We compared the incidence of small bowel within the planning target volume for radiotherapy to the prostate bed in patients who underwent open retropubic and laparoscopic radical prostatectomy., Materials and Methods: A total of 25 patients recently treated with laparoscopic radical prostatectomy prospectively provided consent to undergo radiotherapy planning computerized tomography simulation to assess the incidence of small bowel within the prostate bed planning target volume. These studies were compared to radiotherapy planning computerized tomography in 50 patients who underwent open retropubic radical prostatectomy and received adjuvant or salvage radiotherapy for prostate cancer. For all computerized tomography images 1 blinded observer delineated the distal small bowel loops and 1 blinded radiation oncologist delineated the superior extent of clinical and planning target volumes., Results: The overlap rate between small bowel and planning target volume was 16% in the laparoscopic and open radical prostatectomy groups (p = 0.579)., Conclusions: There is no difference between transperitoneal laparoscopic and open retropubic radical prostatectomy in the incidence of small bowel within the planning target volume for radiotherapy to the prostate bed. Thus, patients who undergo transperitoneal laparoscopic radical prostatectomy do not face a higher risk of toxicity or compromise due to adjuvant or salvage radiotherapy should they require it.

We conducted a genome-wide association study of 3090 sporadic prostate cancer patients and controls using the Affymetrix 10 000 SNP GeneChip. Initial screening of 40 prostate cancer cases and 40 non-cancer controls revealed 237 SNPs to be associated with prostate cancer (P<0.05). Among these SNPs, 33 were selected for further association analysis of 2069 men who had undergone a cancer-screening prostate biopsy. Results identified five loci as being significantly associated with increased prostate cancer risk in this larger sample (rs 1930293, OR=1.7, P=0.03; rs 717809-2p12, OR=1.3, P=0.03; rs 494770-4q34, OR=1.3, P=0.01; rs 2348763-7p21, OR=1.5, P=0.01; rs 1552895-9p22, OR=1.5, P=0.002). To validate these association data, 61 additional HapMap tagSNPs spanning the latter five loci were genotyped in this subject cohort and an additional 1021 men (total subject number=3090). This analysis revealed tag SNP rs 4568789 (chromosome 1q25) and tag SNP rs 13225697 (chromosome 7p21) to be significantly associated with prostate cancer (P-values 0.009 and 0.008, respectively). Haplotype analysis revealed significant associations of prostate cancer with two allele risk haplotypes on both chromosome 1q25 (adjusted OR of 2.7 for prostate cancer, P=0.0003) and chromosome 7p21 (adjusted OR of 1.3, P=0.0004). As linkage data have identified a putative prostate cancer gene on chromosome 1q25 (HPC1), and microarray data have revealed the ETV1 oncogene to be overexpressed in prostate cancer tissue, it appears that chromosome 1q25 and 7p21 may be sites of gene variants conferring risk for sporadic and inherited forms of prostate cancer.

Purpose: Differentiation between Gleason score 6 and 7 in prostate biopsy is important for treatment decision making. Nevertheless, under grading errors compared with the actual pathological grade at radical prostatectomy are common. We compared the characteristics and outcomes of tumors that were scored 6 on prostate biopsy but were 7 on subsequent radical prostatectomy pathological evaluation to those in tumors with a consistent rating of Gleason score 6 or 7 at biopsy and surgery., Materials and Methods: We performed a retrospective database analysis from our referral center (1989 to 2004). We compared pre-prostatectomy characteristics, radical prostatectomy pathological features and the post-radical prostatectomy prostate specific antigen failure rate, defined as any 2 consecutive detectable prostate specific antigen measurements, in 3 subgroups of patients, including 156 with matched Gleason score 6 in the prostate biopsy and radical prostatectomy, 205 with upgraded Gleason score 6/7, that is prostate biopsy Gleason score 6 and radical prostatectomy Gleason score 7, and 412 with matched Gleason score 7 in the prostate biopsy and radical prostatectomy., Results: Radical prostatectomy Gleason score matched the prostate biopsy score in 38.2% of biopsy Gleason score 6 and 81.4% of biopsy Gleason score 7 cases. Higher prostate specific antigen was associated and an increased percent of cancer in the prostate biopsy was predictive of discordance between the prostate biopsy and radical prostatectomy Gleason scores (p <0.001). Margin (p = 0.0075) or seminal vesicle involvement (p = 0.0002), cancer volume (p <0.001) and the prostate specific antigen failures rate (p = 0.014) were significantly higher in under graded Gleason score 7 cancer compared to those in matched Gleason score 6 cases. However, they were comparable to those with a matched Gleason score 7 tumor grade (p = 0.66)., Conclusions: Almost half of tumors graded Gleason score 6 at biopsy are Gleason score 7 at surgery. Upgraded Gleason score 6 to 7 tumors have outcomes similar to those of genuine Gleason score 7 cancer. For prostate biopsy Gleason score 6 tumors clinicians should consider the overall likelihood of tumor upgrading as well as specific patient characteristics, such as prostate specific antigen and the percent of tumor in the prostate biopsy, when contemplating treatments that are optimized for low grade tumors, including watchful waiting or brachytherapy.

Purpose: Random assignment to clinical trials involving different treatment modalities can be difficult. We describe our experience with the Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial (SPIRIT; ACOSOG Z0070 NCIC PR10), a randomized trial for early-stage prostate cancer comparing radical prostatectomy (RP), and brachytherapy (BT). A multidisciplinary educational session was developed to improve patient understanding of treatment options and to facilitate accrual., Patients and Methods: Prostate cancer referrals were screened and men who met favorable risk criteria (T1c/T2a, prostate-specific antigen [PSA] < 10 ng/mL, Gleason < or = 6) were invited to a structured education session before a specialty consultation. Men and their partners viewed the SPIRIT informed-consent video and heard from a cancer patient who described his participation in a randomized trial. Then, a urologist and radiation oncologist together compared and contrasted RP and BT to establish the rationale for the trial., Results: In May 2002, SPIRIT opened for accrual and was endorsed by the University Health Network urologists and radiation oncologists. The first 27 eligible patients were approached about SPIRIT, consulted both specialties, and viewed an educational video. No patients consented. The multidisciplinary education session was then introduced. Forty-seven education sessions with 263 patients resulted in 34 consents. Of 203 patients who were suitable for the study but declined random assignment, 62 chose surgery, 94 chose brachytherapy, three patients chose external radiotherapy, and 11 chose no treatment. Consent rates for eligible and suitable patients were one in six., Conclusion: Men who understand their treatment options and trial rationale as presented jointly by representative specialists from competing treatment modalities may be better equipped to make an informed decision and are more likely to consent to random assignment.

Preclinical studies demonstrate that intratumoral delivery of adenovirus expressing IL-2 eradicates pre-established tumors in mice and confers immune protection from rechallenge. To explore the activity of AdCAIL-2 in prostate cancer, a Phase I clinical trial was conducted in patients with localized disease and Gleason score >7 or prostate-specific antigen (PSA) >10 plus Gleason score 7. A total of 12 patients were injected 4 weeks prior to prostatectomy in a dose-escalation study at doses of 10(9), 5 x 10(9) and 10(10) PFU of virus. No dose-limiting toxicity was observed. Side effects included perineal discomfort, hematuria, flu-like symptoms in two patients and urinary hesitancy in one patient. Pathology demonstrated an inflammatory response consisting predominantly of CD3+CD8+ T lymphocytes with areas of tumor necrosis. Intracellular cytokine staining of tumor-infiltrating lymphocytes demonstrated increases in both gamma-interferon and IL-4 secreting T cells after vaccination. PSA levels fell in five of five evaluable patients treated at the lowest dose (mean decline of 33.3%, range 17-69%). At higher doses, PSA values initially increased after injection, then fell to baseline prior to surgery. This trial demonstrates the feasibility and safety of intraprostatic adenovector-mediated IL-2 gene delivery.

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.

p53 mutation has been shown to be associated with chromosomal instability (CI) in many human dysplastic and neoplastic lesions. However, the precise role of p53 in the pathogenesis of prostate carcinoma (Pca) is unknown. Topographic analysis of p53 alteration using immunohistochemistry (IHC) was performed on 35 archived prostatectomy specimens containing Pca foci; high-grade prostate intraepithelial neoplasia (HPIN) foci intermingled with cancer (HPINI) and situated away (HPINA). Specimens from 2 patients were topographically genotyped using laser capture microdissection, PCR amplification, and direct sequencing of p53 exons 5-9. CI was evaluated in the same tissue foci by interphase in situ hybridization (IFISH) using centromere probes for chromosomes 7, 8, and Y. p53 immunoreactivity was found in 20%, 17%, 0, and 0 in Pca, HPINI, HPINA, and benign epithelium, respectively. p53 molecular analysis in the specimens examined confirmed the IHC findings. IFISH revealed numerical chromosomal alterations in keeping with CI in 71% and 25% of p53+ and p53- Pca, respectively (P =.1), 67% and 0 of p53+ and p53- HPIN, respectively (P <.02), and in 27% and 0 of HPINI and HPINA, respectively. We concluded that p53 mutation is an early change in at least a subset of Pca. HPINI foci tend to have higher overall p53 immunoreactivity and CI than HPINA. The presence of p53 mutation in HPIN was associated with the presence of CI as determined by IFISH. Our study also provided additional evidence in support of the concept that HPIN might be the earliest precursor of cancer. Furthermore, our studies identify genomic similarities in HPINI and Pca, implying that carcinoma may arise from progression of certain HPIN foci that most likely harbor p53 mutation and/or more CI.

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.

Two studies have reported significant associations between susceptibility to prostate cancer and two common missense variants of the HPC2/ELAC2 gene, with estimated relative risks in the range of two- to threefold. We investigated whether these polymorphisms could be informative in the prediction of the presence of prostate cancer in men undergoing prostatic biopsy for the evaluation of an elevated serum-PSA level (> or = 4.0 ng/ml). We genotyped 944 men who underwent a prostate biopsy at our institution, as well as a control population of 922 healthy, unselected women from the same population. The prevalence of the HPC2 Ala541Thr allele was similar in men with prostate cancer (6.3%), men with other prostatic conditions (6.8%), and healthy women (6.3%) (P = .83). We conclude that HPC2 genotyping is unlikely to be a useful adjunct to PSA in the prediction of the presence of biopsy-detected prostate cancer in asymptomatic men.

Objectives: The valine (V) to leucine (L) polymorphism of the SRD5A2 gene is associated with 5-alpha reductase-2 activity; patients with the V allele have high activity and patients with the L allele have low activity. We examined whether this polymorphism predicts the presence of prostate cancer in 320 men without cancer who underwent biopsy and cancer progression in 318 men who underwent radical prostatectomy., Methods: The effect of the SRD5A2 gene in predicting the presence of prostate cancer was examined using logistic regression analysis, controlling for established risk factors. The effect of the SRD5A2 gene in predicting prostate cancer progression was examined using a nested, matched, case-control design. Most of the participants were white., Results: Of the 320 men, 158 (49.4%) were found on biopsy to have prostate cancer. The overall distribution of the V/V, V/L, and L/L genotypes was 47.5%, 42.5%, and 10.0%, respectively. The adjusted odds ratio for having prostate cancer for patients with at least one V allele was 2.53 compared with patients with the L/L genotype (P = 0.03). Of the 318 patients with cancer, 80 had biochemically detected recurrence and 238 had no evidence of recurrence. The odds ratio for progression for patients with at least one V allele was 3.32 (95% confidence interval 1.67 to 6.62, P = 0.0006) compared with patients with the L/L genotype., Conclusions: Men who have the V allele of the SRD5A2 gene have a twofold increase in the risk of prostate cancer development and an additional twofold increase in the risk of progression compared with men with the L/L genotype.

The way in which cytogenetic aberrations develop in prostate cancer (CaP) is poorly understood. Spectral karyotype (SKY) analysis of CaP cell lines has shown that they have unstable karyotypes and also have features associated with chromosomal instability (CIN). To accurately determine the incidence of de novo structural and numerical aberrations in vitro in CaP, we performed SKY analysis of three independent clones derived from one representative cell line, DU145. The frequent generation of new chromosomal rearrangements and a wide variation in the number of structural aberrations within two to five passages suggested that this cell line exhibited some of the features associated with a CIN phenotype. To study numerical cell-to-cell variation, chromosome 8 aneusomy was assessed in the LNCaP, DU145, and PC-3 cell lines and a patient cohort of 15 CaP primary tumors by interphase fluorescence in situ hybridization (FISH). This analysis showed that a high frequency of numerical alteration affecting chromosome 8 was present in both in vitro and in CaP tissues. In comparison to normal controls, the patient cohort had a statistically significant (P<.05), greater frequency of cells with one and three centromere 8 copies. These data suggest that a CIN-like process may be contributing towards the generation of de novo numerical and structural chromosome abnormalities in CaP.

Purpose: The CAG repeat polymorphism of the androgen receptor gene has been associated with an increased prostate cancer risk, and the repeat length correlated with cancer stage and grade at presentation. Men with an allele length of 18 CAG repeats, controlling for grade, stage and serum PSA level at diagnosis using Cox proportional hazard modeling., Results: Overall, the CAG repeat allele was not predictive of recurrence; tumor grade, stage and PSA level at diagnosis were the only predictors of recurrence in a multivariate analysis. However, for patients at low risk for recurrence (Gleason score 2 to 6, stage pT2, and PSA 18 CAG repeats. In contrast, for patients at high risk of recurrence (Gleason score >/= 7, stage pT3/4, or PSA >10 ng./ml.), the relative risk associated with the 18 CAG repeat allele., Conclusions: The length of the CAG repeat polymorphism of the androgen receptor gene may be important for prostate cancer recurrence among patients who are otherwise at low risk for recurrence after radical prostatectomy. These findings have potential implications for patient selection for adjuvant treatment, and for the development of novel treatments.

Purpose: We hypothesize that serum human glandular kallikrein-2 (hK2) levels predict the presence of prostate cancer among men prescreened by prostate-specific antigen (PSA)., Patients and Methods: We conducted a cross-sectional study of 324 men who had no history of prostate cancer and who were referred for prostate biopsy. PSA and hK2 levels were measured using specific nonisotopic immunometric techniques. Cases were patients who were diagnosed with adenocarcinoma of the prostate from biopsy, and controls were patients who had no evidence of cancer from biopsy. The odds ratio for detection of prostate cancer was determined for hK2 measurements, controlling for age, total-PSA level, digital rectal examination, and symptoms of urinary obstruction., Results: Of 324 men, 159 (49.1%) had cancer. Mean hK2 levels and hK2:free-PSA ratios were significantly higher in cases than in controls (1.18 v 0.53 ng/mL, respectively, for hK2, P =.0001; 1.17 v 0.62 for hK2:free-PSA ratio, P =.0001). The crude odds ratio for prostate cancer detection for patients in the highest quartile of hK2 level was 5.83 (95% confidence interval [CI], 2.8 to 12.1; P =.0001) compared with patients in the lowest quartile. The adjusted odds ratio was 6.72 (95% CI, 2.9 to 15.6; P =.0001). Similarly, the crude and adjusted odds ratios for prostate cancer detection using the hK2:free-PSA ratio were 7.36 (95% CI, 3.6 to 15.1; P =.0001) and 8.06 (95% CI, 3. 7 to 17.4; P =.0001), respectively. These odds ratios were higher than that observed for prostate cancer detection by total-PSA level (2.73; P =.03)., Conclusion: Among men prescreened with PSA for prostate cancer, patients with high hK2 measurements have a five- to eight-fold increase in risk for prostate cancer, adjusting for PSA level and other established risk factors. hK2 measurements may be a useful adjunct to PSA in improving patient selection for prostate biopsy.

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.

The rising incidence of and mortality from prostate cancer has generated great interest in improving the results of current methods of treatment. It is well-established that large tumour volumes and positive surgical margins are correlated with higher rates of local failure and distant metastasis. Significant decreases in both tumour volume and the rates of positive surgical margins are seen with NHT. Follow-up data from one randomized trial of hormonal therapy before RT have shown significantly improved disease-free survival, but so far there has been no benefit in overall survival. However, the addition of adjuvant hormonal therapy has been reported to improve survival. The results suggest that neoadjuvant and adjuvant hormonal therapy may be a viable option in men with locally advanced prostate cancer in whom cure is probably impossible, but disease progression can potentially be slowed. What remains to be determined is whether hormonal therapy alone can produce the same results. For younger men with clinically localized prostate cancer, radical prostatectomy is increasingly the treatment of choice. Prospective randomized trials of NHT have produced impressive statistics for decreasing the incidence of positive surgical margins, but the potential to down-stage tumours remains controversial. Follow-up serum PSA measurements have thus far shown no benefit from neoadjuvant therapy. The possibility that patients who fail biochemically, whether they are from the pretreated or control group, may simply represent a subgroup with aggressive tumours that may not respond to androgen withdrawal, has yet to be proved. As more follow-up data are analysed within the next several years, there must be a clear survival advantage if NHT is to be offered as a treatment option. Despite the potential of neoadjuvant therapy, the use of androgen withdrawal before definitive surgical treatment should be limited to clinical trials until a clearer picture emerges. Some may argue that although there is no evidence of a true advantage for NHT, neither is there evidence of harm. However, it must be recognized that androgen withdrawal therapy has side-effects and adds significantly to the overall cost of treatment. Furthermore, NHT delays definitive treatment; clearly, this can be a source of anxiety for the patient and the impact on survival is unknown. Currently, the rates of pathologically organ-confined disease are high in some subsets of patients (e.g. low-stage, low-grade and low PSA) so that NHT is unlikely to have great additional benefit. Although the influence of hormones on prostate growth has been known for many decades, we are only now elucidating the biological mechanisms of hormonal therapy. Although androgen ablation therapy has been used in men with metastatic prostate cancer for more than 50 years, further research at the cellular and molecular level is essential if we are to refine treatment modalities for both localized and advanced disease. Furthermore, until we have more follow-up data from randomized clinical trials of NHT, it cannot be considered part of the standard treatment for carcinoma of the prostate. There are still too many unknown factors; only time will tell if the initial promise of NHT will be fulfilled.

A 65-year-old man undergoes a routine checkup before retiring. His wife has urged him to have his prostate examined, because she has read about testing for prostate cancer and a friend has just died of this disease. During the rectal examination, the man's physician discovers some firmness in the right lobe of the prostate gland. The patient has had no urinary symptoms and is in excellent general health. Sexual function is normal. There is no history of prostate cancer; his father died of a stroke at age 86 years. Testing shows that the patient's prostate-specific antigen level is 9.3 ng/mL, and he is referred to a urologist. Transrectal ultrasound-guided needle biopsy reveals adenocarcinoma with a Gleason score of 7 (intermediate grade). At a follow-up meeting with his physician, the patient says, "I have been doing some research, and it appears that I should have treatment. However, what is less clear to me is what form of therapy is best--surgery or radiation treatment. Please tell me what you can about the state of the art with respect to surgery."

The Prostate Centre, a hypermedia program integrating CD-ROM and Internet technology, was developed to help patients with localized prostate cancer access detailed and current information about available treatment options. Personal interviews with ten patients confirmed the need for more specific information examining the diagnosis and treatment of prostate cancer, as well as the suitability of computers for conveying this information. Sample screen designs effectively determined patients' visual preferences and were a useful springboard for conversation about a number of other relevant topics. Pilot testing of the resulting prototype elicited a positive response about the program from this sample audience. Patients regarded the program as useful, relevant to their needs, and navigable. Although the small sample size limited the study's generalizability, the method of involving patients in the design process successfully guided the program's development toward a greater fit with the users' needs.

Objective: To study the rate of change in prostate specific antigen (PSA velocity) in patients with prostate cancer initially managed by 'watchful waiting'., Patients and Methods: Serial PSA levels were determined in 141 patients with prostate cancer confirmed by biopsy, who were initially managed expectantly and enrolled between May 1990 and December 1995. Sixty-seven patients eventually underwent surgery (mean age 59 years) because they chose it (the decision for surgery was not based on PSA velocity). A cohort of 74 patients remained on 'watchful waiting' (mean age 69 years). Linear regression and logarithmic transformations were used to segregate those patients who showed a rapid rise, defined as a > 50% rise in PSA per year (or a doubling time of < 2 years) and designated 'rapid risers'., Results: An initial analysis based on a minimum of two PSA values showed that 31% were rapid risers. Only 15% of patients with more than three serial PSA determinations over > or = 6 months showed a rapid rise in PSA level. There was no advantage of log-linear analysis over linear regression models., Conclusion: Three serial PSA determinations over > or = 6 months in patients with clinically localized prostate cancer identifies a subset (15%) of patients with a rapidly rising PSA level. Shorter PSA surveillance with fewer PSA values may falsely identify patients with rapid rises in PSA level. However, further follow-up is required to determine if a rapid rise in PSA level identifies a subset of patients with an aggressive biological phenotype who are either still curable or who have already progressed to incurability through metastatic disease.

Purpose: A prospective, multicenter, randomized study was done to test the hypothesis that neoadjuvant androgen withdrawal decreases the incidence of positive margins following radical prostatectomy for localized prostate cancer., Materials and Methods: Observations were made of 213 patients randomized to undergo radical prostatectomy alone (101) or to receive a 12-week course of 300 mg. cyproterone acetate daily followed by surgery (112). Groups were similar at baseline in terms of clinical stage, serum prostate specific antigen and Gleason score. Of 192 patients available for efficacy analysis 9 had stage T1b, 8 stage T1c, 63 stage T2a, 36 stage T2b and 76 stage T2c disease., Results: One or more positive surgical margins were found in 59 of 91 patients (64.8%) in the surgery only group compared to 28 of 101 (27.7%) in the cyproterone acetate group (p = 0.001). Patients who received preoperative therapy had a statistically significantly lower rate of apical margin involvement than those who did not (17.8 versus 47.8%, respectively, p < 0.0001). There was no statistically significant difference in surgical (p = 0.8645) or postoperative (p = 0.173) complications between the 2 groups., Conclusions: Neoadjuvant androgen withdrawal with a 12-week course of 300 mg. cyproterone acetate daily results in a lower rate of positive margins without adversely affecting postoperative recovery. The impact on patient survival will be determined by long-term followup.

Hormone-resistant prostate cancer patients are elderly, frail and in pain. They have a median survival of 6 months. There is no convincing evidence from controlled trials that anything we do will increase life expectancy. Any attempt to do so with currently available agents may either kill them earlier or decrease the quality of the short life left to them. The alternatives for management include the simple, non-toxic, supportive measures of better analgesic use, antiandrogen withdrawal, external beam radiation and steroids, which can produce significant symptomatic improvement. There is little evidence that the benefits of more aggressive therapy exceed those achieved with supportive care.

Twenty-two normal volunteers and 32 patients with either benign prostatic hypertrophy or prostatic carcinoma were examined by magnetic resonance imaging (MRI). The images were of high quality and clearly demonstrated the prostate gland and the surrounding anatomy but were of limited value in differentiating between benign and malignant prostatic disease. Using a specific pulse sequence, the authors were able to visualize what they believed to be the periprostatic venous plexus and suggest that the demonstration of this venous plexus may be of value in showing extraglandular spread of carcinoma of the prostate.