Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Efficacy of vacuum erectile devices (VEDs) after radical prostatectomy: the initial Irish experience of a dedicated VED clinic.

Controversy exists regarding optimal penile rehabilitation program following radical prostatectomy (RP). Vacuum erectile devices (VEDs) have become an important component of penile rehabilitation protocols. The aim of this study was to assess the efficacy and patient satisfaction of a dedicated VED clinic. A voluntary telephone questionnaire was performed of all patients who attended a VED clinic to date in two university teaching hospitals. Patient demographics, histopathological characteristics and functional status (International Index of Erectile Function (IIEF) scores) were obtained from a retrospective review of a prospectively maintained database. Sixty-five men attended the dedicated VED clinic in the two university teaching hospitals. Forty-men (76.3%) men purchased a VED following the dedicated clinic. There was significant differences noted between the mean preoperative and the 3-month postoperative IIEF scores (22.08±3.16 vs 11.3±3.08, P=0.0001) and between the 3-month postoperative IIEF score and the post-VED use IIEF score (11.3±3.08 vs 16.74±2.62, P=0.0001). Despite VED use, there was a significant reduction in erectile function from presurgery status (22.08±3.16 vs 16.74±2.62, P=0.0001). All patients reported that the dedicated VED was helpful and would recommend it to other patients. Our study demonstrates that, despite a reduction in erectile function after RP, successful erections are attainable with a VED. There is potential and need for the development of a standard penile rehabilitation program and treatment of ED after RP internationally.

Pattern of Change in Renal Function Following Radical Nephrectomy for Renal Cell Carcinoma.

Radical nephrectomy (RN) is an independent risk factor for the development of chronic kidney disease (CKD) in those with renal cell carcinoma (RCC). We aimed to examine the pattern of change in post-operative renal function in patients who underwent RN for RCC over a 3 year period at our institution. We performed a retrospective review of histological and biochemical findings in patients undergoing RN for RCC over a 38 month period. Estimated glomerular filtration rate (eGFR) was recorded pre- and post-operatively and at follow-up. We analysed data on 131 patients (median follow-up 24 months). The proportion of patients with advanced CKD increased significantly at follow-up with 48 (85.7%) patients, classified as having stage 2 CKD pre-operatively, being re-classified as stage 3-5. Mean eGFR was significantly lower pre-operatively (76.6 mL/min/1.73 m2) compared to hospital discharge (61 mL/min/1.73 m2, p < 0.001) and follow-up (55.5 mL/min/1.73 m2, p < 0.001). Those with pT1 tumours sustained a significantly greater decline in eGFR compared to other stages. In conclusion, patients with pT1 a and pT1 b tumours sustain a disproportionate decline in renal function and may benefit the most from NSS.

Prostate cancer risk assessment tools in an unscreened population.

OBJECTIVE: To compare the prostate cancer prevention trial risk calculator (PCPT-RC) and European randomized study of screening for prostate cancer risk calculator (ERSPC-RC) in a unique unscreened population from the West of Ireland. PATIENTS AND METHODS: Data was prospectively recorded for all 556 consecutive men who underwent prostate biopsy at our institution as part of the Rapid Access Prostate Assessment Clinic program in Ireland. The estimated probabilities of detecting prostate cancer and high-grade disease were calculated using the PCPT and ERSPC risk calculators. For each calculator the discriminative ability, calibration and clinical utility was assessed. RESULTS: Prostate cancer was detected in 49% and high-grade prostate cancer in 34% of men. Receiver operating characteristic curve analysis demonstrated that the PCPT-RCs outperformed the ERSPC-RCs for the prediction of prostate cancer areas underneath the ROC curve (AUC 0.628 vs. 0.588, p = 0.0034) and for the prediction of high-grade prostate cancer (AUC 0.792 vs. 0.690, p = 0.0029). Both risk calculators generally over-predicted the risk of prostate cancer and high-grade disease across a wide range of predicted probabilities. Decision curve analysis suggested greater net benefit using the PCPT-RCs in this population. CONCLUSIONS: Multivariable nomograms can further aid patient counselling for early prostate cancer detection. In unscreened men from Western Ireland, the PCPT-RCs provided better discrimination for overall prostate cancer and high-grade disease compared to the ERSPC-RC. However, both tools overpredicted the risk of cancer detection on biopsy, and it is possible that a different set of predictive variables may be more useful in this population.

Audit of rapid access introduction reveals high prevalence of prostate cancer in Western Region.

INTRODUCTION: Men with symptoms suggestive of prostate cancer are now directly referred by their general practitioners to rapid access prostate assessment clinics (RAPACs). This service implements recommendations outlined by the National Cancer Control Programme. The RAPAC was introduced at Galway University Hospital, Galway, Ireland in June 2009, aiming to structure GP referral of patients with suspected prostate cancer to a urology service. AIMS: The aims of this study are to assess our initial experience with particular emphasis on access times, patient demographics, detection rates and treatment outcomes. METHODS: Data on all patients presenting to the RAPAC during the preliminary 2-year period have been gathered prospectively and analysed using standard parametric analysis methods. RESULTS: A total of 1,106 patients were reviewed at 278 clinic sessions during the initial 2-year period. The average waiting time to first clinic visit was 18 days (12-39 days). The mean age of referral to the clinic is 65 years (44-88 years). The mean PSA is 16.31 g/dL (0.4-845 g/dL). Of the 1106 patients undergoing TRUS biopsies, 503 (45.5 %) patients were diagnosed with prostate cancer. Further analysis patient demographics and cancer grading is presented in the article. Seventy-one patients (14.1 %) underwent radical retropubic prostatectomy. Sixty-seven patients (13.3 %) are being followed on an active monitoring programme, whilst 235 (56.7 %) received primary treatment with external beam radiotherapy and 68 (13.5 %) received brachytherapy. CONCLUSION: This data highlight the necessity of a RAPAC to streamline the provision of prostate cancer services in the west of Ireland.

Matrix metalloproteinases (MMPs) in bladder cancer: the induction of MMP9 by epidermal growth factor and its detection in urine.

OBJECTIVES: To investigate the matrix metalloproteinases (MMPs) 2 and 9 in bladder cancer cell lines stimulated with epidermal growth factor (EGF), and to investigate the presence of gelatinases in the urine of patients with bladder tumours, in relation to the stage and grade of tumour and the EGF receptor (EGFR) status. PATIENTS, SUBJECTS AND METHODS: Conditioned media from cultured tumour cells were analysed by zymography. Urine samples from 28 patients with transitional cell carcinoma and 12 normal volunteers were also analysed. Western blotting was used to verify the bands of gelatinolytic activity. The EGFR status of the tumours was assessed by immunohistochemistry. RESULTS: MMP9 was induced by EGF in the RT112 but not the RT4 bladder tumour cell line, whereas MMP2 production was unaffected by EGF. Gelatin zymography of urine samples from patients with bladder tumours showed high levels of MMP activity, with 78% positive for MMP9 and 28% positive for MMP2. The total gelatinolytic and MMP9 activity were significantly higher in patients with high-stage invasive tumours than in those with superficial tumours (P < 0.05), and were higher than in normal controls. Gelatinolytic activity at 130 and 200 kDa in urine was identified as MMP9 and MMP2. There was no significant relationship of urinary MMP9 activity to EGFR status of the tumour. CONCLUSION: EGF induces MMP9 but not MMP2 in bladder cells. Analysis of urinary gelatinases is a useful noninvasive technique and both total gelatinase and MMP9 activity are associated with high stages of bladder tumours.

Improving prostate cancer detection with an extended-core transrectal ultrasonography-guided prostate biopsy protocol.

OBJECTIVE: To investigate whether taking two transition zone (TZ) and four lateral peripheral zone (PZ) biopsies in addition to routine parasaggital sextant biopsies would improve detection rates in men with suspected prostate cancer. PATIENTS AND METHODS: The study included 493 consecutive men (mean age 68.7 years, sd 8.2) with elevated serum prostate-specific antigen (PSA) levels and/or abnormal findings on a digital rectal examination who underwent transrectal ultrasonography-guided prostate biopsy. In addition to sextant biopsies, six further biopsies were obtained, two from the TZ (mid-gland) and four from the lateral PZ (base and mid-gland). Pathological findings for the additional biopsies were compared with those of the sextant regions. RESULTS: Prostatic adenocarcinoma was diagnosed in 164 of the 493 (33%) men biopsied. Men with cancer were older, had smaller prostates and higher median PSA levels than men with negative biopsies. Sextant biopsies were positive for cancer in 133 of 164 (81%) men. All three sets of biopsies were positive in 53 (32%) cases. In 50 (30%) men both the sextant and lateral PZ biopsies were positive, while in six (4%) men, both sextant and TZ biopsies were positive. Thirty-one (19%) tumours were not detected by sextant biopsies, 10 (6%) where the lateral PZ biopsies alone were positive, 17 (10%) where the TZ biopsies alone were positive and four (3%) where both the TZ and lateral PZ together were positive. There were no differences in median PSA concentration, total prostate volume or TZ volume between men with an isolated TZ cancer and men with cancer elsewhere in the prostate. However, 77% of men with TZ cancer had a PSA of > 10 ng/mL, compared with 60% of men with cancer at other sites within the prostate (P = 0.015). CONCLUSION: An extended-core biopsy protocol significantly improves the detection rate for prostate cancer when compared with the standard sextant biopsy protocol alone. Routine TZ biopsies should be considered for men with serum PSA levels of >10 ng/mL.

Prognostic significance of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in voided urine samples from patients with transitional cell carcinoma of the bladder.

PURPOSE: To study the role of urinary matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in bladder cancer and their relationship to tumor progression. EXPERIMENTAL DESIGN: MMP-1 and TIMP-1 were measured by ELISA in urine samples from 131 patients with bladder tumors (7 cis, 74 Ta, 29 T1, and 21 T2-T4; 46 G(1), 41 G(2), and 37 G(3)), 5 patients with prostate cancer, 33 patients with benign lower urinary tract disorders, and 36 healthy volunteers. Complete clinical data were available for 100 patients with bladder cancer with a median follow-up time of 24 months (range: 4-39 months). RESULTS: MMP-1 was detected in urine samples from 21 of 131 (16%) patients with bladder cancer but was undetectable in samples from all other groups (P < 0.0001). Urinary MMP-1 was detected in a higher percentage of patients with T2-T4 tumors and G(3) tumors than patients with cis/Ta/T1 or G(1)-G(2) tumors (P = 0.04 and P = 0.0074, respectively). Patients with detectable concentrations of urinary MMP-1 had higher rates of disease progression (P = 0.04) and death from bladder cancer (P = 0.02) than patients with undetectable urinary MMP-1. All patient groups had higher urinary TIMP-1 concentrations than healthy volunteers (P = 0.02). Patients with muscle-invasive tumors had higher concentrations of urinary TIMP-1 than patients with cis/Ta/T1 tumors (P = 0.037), but there was no association between TIMP-1 and tumor grade. Urinary TIMP-1 levels strongly correlated with tumor size (P = 0.0002). Progression-free survival rates were lower for patients with urinary TIMP-1 concentrations above the median (1.8 ng/ml, P = 0.04), but urinary TIMP-1 levels were not related to disease-specific survival. Patients with T2-T4 tumors and G(3) tumors had significantly lower urinary MMP-1:TIMP-1 ratios than patients with Ta/T1 bladder tumors (P = 0.039) or G(1)-G(2) tumors (P = 0.0415). CONCLUSIONS: Where urinary MMP-1 is detectable, the patient is more likely to have a bladder tumor of advanced stage or grade and may be at increased risk of disease progression and death of bladder cancer. The relationship between urinary TIMP-1, muscle-invasion, and disease progression in bladder cancer is at variance with its role as an inhibitor of MMPs and warrants additional evaluation.

Caveolin-1 expression is associated with high-grade bladder cancer.

OBJECTIVES: To assess the levels of caveolin-1 in a series of bladder tumor specimens of varying stage and grade and to identify possible links between caveolin-1 status and clinical behavior. Caveolae have emerged as sites of important regulatory events at the cell membrane in many different cell types. Caveolins are the main structural components of caveolae and belong to a family of highly conserved integral membrane proteins. The function of caveolin-1 appears to be intrinsically linked to cell signaling modulation by multiple pathways. Modification of CAV-1 gene expression appears to be a common feature of the oncogenically transformed phenotype. METHODS: Using a rabbit polyclonal antibody against caveolin-1 and immunohistochemistry, we assessed caveolin-1 protein expression in 89 formalin-fixed, paraffin-embedded bladder tumor sections. The patient group studied included 71 men and 18 women (mean age +/- SD 69.7 +/- 10.9 years). The stage was Ta-T1 in 68 and T2-T4 in 21 tumors in this series. The clinical follow-up was 1 to 38 months (mean 21.2 +/- 9.9). RESULTS: A statistically significant association was observed between caveolin-1 immunoreactivity and tumor grade (P = 0.0118, chi-square test), with 8 (21%) of 38 G3, 1 (3%) of 30 G2, and 0 of 21 G1 tumors positive for caveolin-1. When the clinical data were examined in conjunction with caveolin-1 status, no statistically significant relationship was seen between caveolin-1 expression and tumor multiplicity, tumor recurrence, tumor progression, or patient survival. CONCLUSIONS: The results of our study demonstrate that altered expression of caveolin-1 protein is a component of tumor dedifferentiation in a subset of high-grade bladder cancers. This pilot study provides a basis for further investigation of the role of caveolin-1 and the function of caveolae in the most aggressive forms of this tumor.

Diagnostic dilemmas in detection of prostate cancer in patients undergoing transrectal ultrasound-guided needle biopsy of the prostate.

Transrectal ultrasound (TRUS)-guided needle biopsy of the prostate is a widely practised method for obtaining high quality tissue cores for histological diagnosis in men with suspected prostate cancer. Technological advances such as high-resolution hand held probes with biplanar imaging capabilities and spring-loaded needles that easily permit multiple biopsies to be obtained have ensured that this technique has rightly taken its place at the forefront of prostate cancer diagnosis. However, the capacity for TRUS to identify prostate cancer remains limited because of poor specificity and variability in the ultrasonic appearance of tumours. Widespread prostate-specific antigen (PSA) testing has increasingly resulted in greater numbers of tumours being diagnosed at an early stage, when they are clinically impalpable and ultrasonically indistinguishable from surrounding normal prostate tissue. In this setting, the principal role for TRUS is to facilitate systematic sampling of all relevant zones of the prostate. Despite advances in technology and in our understanding of this disease, a number of diagnostic dilemmas arise. Should we perform lesion-directed or random biopsies? How many tissue cores should be obtained for optimal diagnostic yield, to reduce the incidence of false-negative biopsies? What areas of the prostate should be biopsied to give the best diagnostic results? If the initial biopsies fail to detect cancer, who should undergo repeat biopsy? Some have also voiced concern that TRUS risks identifying clinically insignificant disease. Here, we review the studies that have addressed these issues and have lead to the evolution of TRUS-guided prostate biopsy into an essential tool in the detection of carcinoma of the prostate. Prostate Cancer and Prostatic Diseases (2000) 3, 13-20

Elevated serum prostate specific antigen levels in conjunction with an initial prostatic biopsy negative for carcinoma: who should undergo a repeat biopsy?

OBJECTIVE: To determine the outcome of repeated prostatic biopsies in men attending with suspected prostate cancer but an initial negative biopsy. PATIENTS AND METHODS: Patients who had undergone two or more transrectal ultrasonography (TRUS)-guided prostate biopsies were identified from the Hospital Information Support System database. Indications for TRUS were a raised prostate-specific antigen (PSA) level (>4.0 ng/mL), with or without an abnormal digital rectal examination (DRE). Sextant prostate biopsies plus biopsies of any suspicious hypoechoic area or area of DRE abnormality were obtained for histology. Forty-eight patients underwent repeat TRUS-guided prostatic biopsies (mean age 67.5, sd 7. 25, range 53-82 years). RESULTS: The mean (sd, median, range) PSA level was 16.9 (13.5, 11.6, 5.2-61.8) ng/mL. Fifteen patients (31%) had carcinoma on repeat biopsy, 11 after the second and four after a third biopsy. The positive repeat biopsy rate was 24% where the PSA level was 4.0-9.9 ng/mL, 33% if the level was 10.0-19.9 ng/mL and 39% if it was >/=20.0 ng/mL. There was no significant difference in age or initial PSA concentration between those men with positive and those with negative repeat biopsies. However, patients with cancer had significantly higher PSA levels before repeat biopsy than at first biopsy (P=0.0043) and had greater PSA velocities than had patients with no diagnosis of cancer (P=0.0067). CONCLUSION: Where sufficient clinical suspicion exists, despite an initial negative biopsy, repeat TRUS-guided prostate biopsies should be carried out to exclude carcinoma of the prostate.

The impact of transurethral resection of bladder tumour on serum levels of soluble E-cadherin.

OBJECTIVE: To evaluate soluble E-cadherin (sE-cadherin) as a potential tumour marker in patients with transitional cell carcinoma (TCC) of the bladder (previously shown to correlate with tumour grade, number of Ta/T1 tumours at presentation and a positive 3-month check cystoscopy) by assessing its serum concentration in relation to transurethral resection of bladder tumour (TURBT). PATIENTS AND METHODS: Samples of venous blood were obtained from 25 patients with bladder cancer: (i) before cystoscopy/TURBT: (ii) intraoperatively, during tumour resection; and (iii) on the first day after surgery. Levels of sE-cadherin were measured using an enzyme-linked immunosorbent assay. RESULTS: Sixty-three serum samples from patients with TCC of the bladder were available for analysis (23 before, 21 during and 19 after surgery). Patients with G2/3 tumours had significantly higher median preoperative levels of sE-cadherin (16.37 and 13.03 microg/mL, respectively) than those with G1 tumours (9.493 microg/mL; P = 0.0164). There was no correlation between tumour stage and preoperative sE-cadherin concentration. The median concentrations of sE-cadherin were not significantly different before, during and after TURBT. CONCLUSIONS: This study confirmed the previous finding that higher levels of serum sE-cadherin correlate with increasing tumour grade but not with clinicopathological stage. Serum sE-cadherin levels are not significantly altered by TURBT in the immediate perioperative period.