Michael Stoeckle

Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone.

BACKGROUND Abiraterone, an androgen synthesis inhibitor, has been successfully used in the treatment of castration-resistant prostate cancer (CRPC) for 2 yr. Enzalutamide is a second-generation nonsteroidal antiandrogen that has recently been approved for the same indication. OBJECTIVE This is the first study to evaluate the effectiveness of enzalutamide after failure of abiraterone. DESIGN, SETTING, AND PARTICIPANTS Thirty-five patients were identified as having received sequential therapy with abiraterone followed by enzalutamide. All patients had undergone prior docetaxel chemotherapy, and no patient had received ketoconazole. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Posttreatment changes in prostate-specific antigen (PSA) were used to determine the activity of enzalutamide in patients who had received prior abiraterone. RESULTS AND LIMITATIONS The median duration of abiraterone treatment was 9.0 mo (range: 2.0-19.0 mo). Of the 35 patients, 16 (45.7%) achieved a >50% decline in PSA, and 14 (40%) had a rising PSA as the best response. The median duration of subsequent enzalutamide treatment was 4.9 mo (Kaplan-Meier estimate; 95% confidence interval [CI], 2.4-7.4). Seven of 16 CRPC patients who were initially abiraterone-sensitive (43.8%) and 3 of 19 CRPC patients who were initially abiraterone-insensitive (15.8%) showed a >50% PSA decline while taking enzalutamide. Of the 35 patients, 17 (48.6%) were primarily enzalutamide-resistant and showed a rising PSA as the best response. Median time to progression was 4.0 mo (95% CI, 2.0-6.0) for 18 of 35 patients with at least one declining PSA value while taking enzalutamide (51.4%). Of the 17 patients who were assessable radiologically, only 1 (2.9%) attained a confirmed partial response. Small sample size was the major limitation. CONCLUSIONS Enzalutamide treatment achieved only a modest response rate in patients progressing after abiraterone. Although cross-resistance between abiraterone and enzalutamide was a common phenomenon, it was not inevitable, and a small but significant number of patients showed significant benefit from sequential treatment.

Analysis of intracorporeal compared with extracorporeal urinary diversion after robot-assisted radical cystectomy: Results from the international robotic cystectomy consortium

BACKGROUND Intracorporeal urinary diversion (ICUD) has the potential benefits of a smaller incision, reduced pain, decreased bowel exposure, and reduced risk of fluid imbalance. OBJECTIVE To compare the perioperative outcomes of patients undergoing extracorporeal urinary diversion (ECUD) and ICUD following robot-assisted radical cystectomy (RARC). DESIGN, SETTING, AND PARTICIPANTS We reviewed the database of the International Robotic Cystectomy Consortium (IRCC) (18 international centers), with 935 patients who had undergone RARC and pelvic lymph node dissection (PLND) between 2003 and 2011. INTERVENTION All patients within the IRCC underwent RARC and PLND as indicated. The urinary diversion was performed either intracorporeally or extracorporeally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Demographic data, perioperative outcomes, and complications in patients undergoing ICUD or ECUD were compared. All patients had at least a 90-d follow-up. The Fisher exact test was used to summarize categorical variables and the Wilcoxon rank sum test or Kruskal-Wallis test for continuous variables. RESULTS AND LIMITATIONS Of 935 patients who had RARC and PLND, 167 patients underwent ICUD (ileal conduit: 106; neobladder: 61), and 768 patients had an ECUD (ileal conduit: 570; neobladder: 198). Postoperative complications data were available for 817 patients, with a minimum follow-up of 90 d. There was no difference in age, gender, body mass index, American Society of Anesthesiologists grade, or rate of prior abdominal surgery between the groups. The operative time was equivalent (414 min), with the median hospital stay being marginally longer for the ICUD group (9 d vs 8 d, p=0.086). No difference in the reoperation rates at 30 d was noted between the groups. The 90-d complication rate was not significant between the two groups, but a trend favoring ICUD over ECUD was noted (41% vs 49%, p=0.05). Gastrointestinal complications were significantly lower in the ICUD group (p ≤ 0.001). Patients with ICUD were at a lower risk of experiencing a postoperative complication at 90 d (32%) (odds ratio: 0.68; 95% confidence interval, 0.50-0.94; p=0.02). Being a retrospective study was the main limitation. CONCLUSIONS Robot-assisted ICUD can be accomplished safely, with comparable outcomes to open urinary diversion. In this cohort, patients undergoing ICUD had a relatively lower risk of complications.

Novel amplification unit at chromosome 3q25-q27 in human prostate cancer.

In prostate carcinoma, amplification of the genes c‐MYC, Her2/NEU, and the androgen receptor gene has been documented, with gene amplification being related to progressive tumor growth. Recently, using comparative genomic hybridization (CGH), we provided evidence for DNA copy number gains at chromosome 3q25–q26 in prostate cancer [Sattler et al.: Prostate 39:79–86, 1999].

Long-term Oncologic Outcomes Following Robot-assisted Radical Cystectomy: Results from the International Robotic Cystectomy Consortium

BACKGROUND Long-term oncologic data on patients undergoing robot-assisted radical cystectomy (RARC) are limited and based largely on single-institution series. OBJECTIVE Report survival outcomes of patients who underwent RARC ≥5 yr ago. DESIGN, SETTING, AND PARTICIPANTS Retrospective review of the prospectively populated International Robotic Cystectomy Consortium multi-institutional database identified 743 patients with RARC performed ≥5 yr ago. Clinical, pathologic, and survival data at the latest follow-up were collected. Patients with palliative RARC were excluded. Final analysis was performed on 702 patients from 11 institutions in 6 countries. INTERVENTION RARC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Outcomes of interest, recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were plotted using Kaplan-Meier survival curves. A Cox proportional hazards model was used to identify factors that predicted outcomes. RESULTS AND LIMITATIONS Pathologic organ-confined (OC) disease was found in 62% of patients. Soft tissue surgical margins (SMs) were positive in 8%. Median lymph node (LN) yield was 16, and 21% of patients had positive LNs. Median follow-up was 67 mo (interquartile range: 18-84 mo). Five-year RFS, CSS, and OS were 67%, 75%, and 50%, respectively. Non-OC disease and SMs were associated with poorer RFS, CSS, and OS on multivariable analysis. Age predicted poorer CSS and OS. Adjuvant chemotherapy and positive SMs were predictors of RFS (hazard ratio: 3.20 and 2.16; p<0.001 and p<0.005, respectively). Stratified survival curves demonstrated poorer outcomes for positive SM, LN, and non-OC disease. Retrospective interrogation and lack of contemporaneous comparison groups that underwent open radical cystectomy were major limitations. CONCLUSIONS The largest multi-institutional series to date reported long-term survival outcomes after RARC. PATIENT SUMMARY Patients who underwent robot-assisted radical cystectomy for bladder cancer have acceptable long-term survival.

Development of a standardised training curriculum for robotic surgery: a consensus statement from an international multidisciplinary group of experts

To explore the views of experts about the development and validation of a robotic surgery training curriculum, and how this should be implemented.

Telomerase Activity and Telomerase Subunit Gene Expression Levels Are Not Related in Prostate Cancer: A Real-Time Quantification and In Situ Hybridization Study

Because the mechanisms of telomerase activation in prostate cancer are mainly unknown, we investigated the relationships between telomerase activity and expression levels of human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) mRNA in benign and malignant alterations of the human prostate gland. Using the LightCycler technology, hTERT mRNA expression was quantified in 46 radical prostatectomy and 10 benign prostatic hyperplasia (BPH) cases; hTR expression was quantified in a subset of these tissue samples. Telomerase activity was measured using a quantitative telomeric repeat amplification protocol ELISA assay. Similar to hTR, which was expressed in all tissue samples tested, hTERT mRNA was detected in 98% of the prostate cancer samples and in 30% of the BPH samples. Regarding clinicopathologic variables, telomerase activity was significantly correlated with Gleason score (<7 vs ≥7, p = 0.02). No relationships emerged between normalized hTR or hTERT expression levels and tumor stage, Gleason score, lymph node status, or preoperative serum prostate-specific antigen. Remarkably, one third of all cancer and BPH tissue samples with hTR and hTERT expression lack telomerase activity. Quantitative analyses contradict the assumption that a certain threshold level of hTR or hTERT mRNA is required for telomerase activation, thus indicating that telomerase regulation in prostate cancer occurs more likely on a posttranscriptional level. Nevertheless, the observation that hTR and hTERT mRNA levels are significantly (p < 0.002) correlated suggests some common mechanisms in the up-regulation of hTR and hTERT expression. Because in situ hybridization revealed strong hTERT expression in all cells of the tumor glands but also in high-grade prostatic intraepithelial neoplasia foci, this up-regulation seems to occur early in prostate carcinogenesis.

Long-term Survival in Bilateral Renal Cell Carcinoma : A Retrospective Single-Institutional Analysis of 101 Patients After Surgical Treatment

OBJECTIVES Bilateral renal cell carcinomas (bRCC) account for <4% of all renal tumors. We report on the management, histopathologic results, and long-term follow-up of 101 patients with bRCC. METHODS A total of 101 patients with bRCC who had undergone surgery from 1975 to 2005 at our institution were identified from our kidney tumor database and included in this retrospective analysis. Cancer-specific survival was assessed using the Kaplan-Meier method. Subgroups were compared using the log-rank test. Statistical analysis was performed with the Statistical Package for Social Sciences for Windows. RESULTS Of 3097 kidney tumor patients, 101 (3.3%) had bRCC on final histopathologic examination. Synchronous tumors were found in 43 patients (42.6%) and metachronous tumors in 58 (57.4%). The cancer-specific survival rate of the entire cohort was 91.9%, 79.1%, and 56.7% after 5, 10, and 20 years, respectively. The survival of patients with synchronous or metachronous bRCCs did not differ significantly. Patients with metachronous bRCC were significantly younger at first diagnosis than those with synchronous bRCCs (median age 53.6 vs 58.7 years, P < .05). The histopathologic results revealed significantly greater rates of papillary bRCCs in synchronous tumors (P < .05). CONCLUSIONS Standardized techniques of nephron-sparing surgery can achieve excellent survival rates in bRCC. Among other arguments for nephron-sparing surgery, kidney-preserving strategies are of particular importance in younger patients with unilateral RCC against the background of an increasing risk of developing a contralateral neoplasm with older age.

Clinical differences in daytime wetting subtypes: urge incontinence and postponed voiding.

PURPOSE Urge incontinence and voiding postponement are common subtypes of daytime wetting in children. We analyzed clinical and behavioral differences in children with urge incontinence, voiding postponement and healthy controls at 2 centers. MATERIALS AND METHODS A total of 49 consecutive children 5 to 13 years old with urge incontinence (22) or voiding postponement (27) who presented to the department of urology or child psychiatry were examined as well as 32 age and gender matched controls. Instruments included physical examination, sonography, uroflowmetry, urinalysis, a 48-hour bladder diary, the Child Behavior Checklist, a structured psychiatric interview and an intelligence test. RESULTS The incontinent group consisted of 28 boys and 21 girls with a mean age of 7.35 years. Controls included 13 girls and 19 boys with a mean age of 7.31 years. Incontinent children had a higher rate of pathological uroflow curves (33% vs 25%) and urinary tract infection (6% vs 3%), greater post-void residual volume (6.3 ml vs 3.8 ml) and a thicker bladder wall. Mean IQ was the same in the 2 groups (103). The Child Behavior Checklist showed that significantly more incontinent children had clinical total behavior (41% vs 9%, p <0.01), and externalizing (35% vs 0%, p <0.001) and internalizing (29% vs 6%, p <0.05) scores than controls. Also, more children with voiding postponement had total clinical scores than those with urinary incontinence (56% vs 24%, p <0.05). Of incontinent children 49% fulfilled the criteria for at least 1 ICD-10 psychiatric diagnosis vs 9% of controls (p <0.001). There were no differences between children recruited at the departments of urology and child psychiatry. CONCLUSIONS This study shows that urge incontinence and voiding postponement are significantly associated with somatic complaints and psychological abnormalities compared to a control population. Children with voiding postponement have more externalizing behavioral disorders. Children seen at urological departments carry the same psychiatric risks and require the same attention to behavioral problem diagnosis.

Age Dependent Secretion of LH and ACTH in Healthy Men and Patients with Erectile Dysfunction

OBJECTIVES Age dependent secretion of testicular and adrenal androgens was examined in healthy men and patients with erectile dysfunction (ED). METHODS In 95 healthy men (age 20-74 years) and 739 patients with ED, luteineizing hormone (LH, n = 739), adrenocorticotropic hormone (ACTH, n = 480) and the secretion products of testis and adrenal gland testosterone (T, n = 750), free testosterone (fT, n = 718), dehydroepiandrosteronesulfate (DHEAS, n = 598) and cortisol (n = 538) were measured. RESULTS In healthy men, LH was measured from 0.75-8.58 mIU/ml and ACTH from 10.59-121.7 pg/ml. Statistically, age was not correlated to LH (P = 0.573) and ACTH (P = 0.833) in healthy men. The secretion products T (P < 0.05), fT (P < 0.001), DHEAS (P < 0.001) and cortisol (P < 0.05) declined significantly with age in healthy persons. In patients with ED, a significant age dependent increase of LH (P < 0.05, n = 739), but not ACTH (P = 0.469, n = 480) was found. T (P < 0.001, n = 736), fT (P < 0.001, n = 718) and DHEAS (P < 0.001, n = 598), but not cortisol (P = 0.307, n = 538) declined in age dependent patients with ED. Age matching revealed a statistical significant elevation (P < 0.05) only for LH (n = 659) in comparison to healthy men (n = 94), all other hormones were not different in both groups. CONCLUSION An LH-increase in patients with erectile dysfunction underlines the importance of Leydig cell degeneration in this disease, but age dependent decline of T secretion was comparable to healthy men, demonstrating a working hypophyseal-testicular-axis. Indication of androgen replacement is therefore limited to selected cases.

Randomized phase III study of adjuvant versus progression-triggered treatment with gemcitabine (G) after radical cystectomy (RC) for locally advanced bladder cancer (LABC) in patients not suitable for cisplatin-based chemotherapy (CBC) (AUO-trial AB22/00).

250 Background: Cisplatin-based chemotherapy (CBC) has been widely used in trials of adjuvant therapy for LABC after RC. A high proportion of patients are unfit for CBC after RC for LABC. We therefore performed a prospective randomized phase III trial on G-monotherapy administered as adjuvant therapy (G-adj) vs in case of progression (G-prog) in pts not suitable for CBC. METHODS Between 7/2000 and 12/2008 120 of 178 planned pts with LABC unfit for CBC were randomized between 6 adjuvant cycles of G (q3w) starting within 12 wks after RC and G in case of disease progression. The primary endpoint of the trial was progression-free survival (PFS). Secondary endpoints included cancer-specific (CSS) and overall survival (OS) as well as treatment related toxicity. RESULTS The trial of 178 planned pts was closed early due to slow accrual. Of 120 randomized pts from 29 centers 114 were eligible for analysis. Median age of 81 male and 33 female pts was 72 (45-82) years. Lymph-node positive disease was found in 52/114 (47%) of pts at the time of surgery. The intention-to-treat analysis demonstrated a 10% difference in PFS after 3 years 50% (G-adj) vs 40% (G-prog) with a median PFS of 23 mo (G-adj) vs 17 mo (G-prog). The difference in PFS was not statistically significant (nss) (p= 0.335; HR 1.375, 95%CI 0.719 - 2.627). CSS at 3ys: 56% (G-adj) vs 50% (G-prog) with a median CSS of 49 mo (G-adj) vs 38 mo (G-prog). The difference in CSS was nss (p= 0.622; HR 1.166, 95%CI 0.632 - 2.149). OS at 3ys: 49% (G-adj) vs 48% (G-prog) with a median OS of 32 mo (G-adj) vs 31 mo (G-prog). The difference in OS was nss (p= 0.426; HR 1.225, 95%CI 0.743 - 2.018). Treatment with G was usually well tolerated, with less than 15% grade 3/4 toxicities..There was one treatment related death in the G-adj arm. CONCLUSIONS The study-hypothesis of a 15% difference in PFS after 3 years in favor of G-adj vs G-prog could not be confirmed. Nevertheless a marked difference in survival in favor of G-adj was shown by Kaplan-Meier plots regarding PFS, CSS and OS within the first 24 months after RC. CLINICAL TRIAL INFORMATION NCT00146276.