Vincent Ravery

PROSPECTIVE EVALUATION OF PROSTATE CANCER DETECTED ON BIOPSIES 1, 2, 3 AND 4: WHEN SHOULD WE STOP?

PURPOSE We evaluated biochemical parameters and pathological features, as well as biopsy related morbidity of prostate cancer detected on biopsies 2, 3 and 4 in men with total serum prostate specific antigen (PSA) between 4 and 10 ng./ml. These features were compared to those detected on prostate biopsy 1. MATERIALS AND METHODS In this prospective European Prostate Cancer Detection study 1,051 men with total PSA between 4 and 10 ng./ml. underwent transrectal ultrasound guided sextant biopsy and 2 additional transition zone biopsies. All patients in whom biopsy samples were negative for prostate cancer underwent biopsy 2 after 6 weeks. If also negative, biopsies 3 and even 4 were performed at 8-week intervals. Those patients with clinically localized cancer underwent radical prostatectomy. Pathological and clinical features of patients diagnosed with cancer on either biopsy 1 or 2 and clinically organ confined disease who agreed to undergo radical prostatectomy were compared. RESULTS Cancer detection rates on biopsies 1, 2, 3 and 4 were 22% (231 of 1,051), 10% (83 of 820), 5% (36 of 737) and 4% (4 of 94), respectively. Overall, of the patients with clinically localized disease, which was 67% of cancers detected, 86% underwent radical prostatectomy and 14% opted for watchful waiting or radiation therapy. Overall, 58.0%, 60.9%, 86.3% and 100% of patients had organ confined disease on biopsies 1, 2, 3 and 4, respectively. Despite statistically significant differences in regard to multifocality (p = 0.009) and cancer location (p = 0.001), including cancer on biopsy 2 showing a lower rate of multifocality and a more apico-dorsal location, there were no differences in regard to stage (p = 0.2), Gleason score (p = 0.3), percent Gleason grade 4/5 (p = 0.2), serum PSA and patient age between biopsies 1 and 2. However, cancer detected on biopsies 3 and 4 had a significantly lower Gleason score (p = 0.001 and 0.001), lower rate of grade 4/5 (p = 0.02), and lower volume (p = 0.001 and 0.001) and stage (p = 0.001), respectively. CONCLUSIONS Despite differences in location and multifocality, pathological and biochemical features of cancer detected on biopsies 1 and 2 were similar, suggesting comparable biological behaviors. Cancer detected on biopsies 3 and 4 had a lower grade, stage and volume compared with that on biopsies 1 and 2. Morbidity on biopsies 1 and 2 was similar, whereas biopsies 3 and 4 had a slightly higher complication rate. Therefore, biopsy 2 in all cases of a negative finding on biopsy 1 appears justified. However, biopsies 3 and 4 should only be obtained in select patients with a high suspicion of cancer and/or poor prognostic factors on biopsy 1 or 2.

EXTENSIVE BIOPSY PROTOCOL IMPROVES THE DETECTION RATE OF PROSTATE CANCER

PURPOSE We evaluated improvement in the rate of prostate cancer detection when using an extensive biopsy protocol involving peripheral cores. MATERIALS AND METHODS We prospectively evaluated 303 consecutive men who underwent transrectal ultrasound guided biopsy due to elevated prostate specific antigen (PSA) and/or abnormal digital rectal examination. Ten biopsies were performed, including at least 5 at the base and middle of each lobe. In addition to standard biopsy at a 45-degree angle, a more peripheral 30-degree angle biopsy was obtained. At the apex only 1 standard biopsy was done. However, when prostate volume was greater than 50 cm.3, an additional peripheral biopsy was obtained at the apex. RESULTS The complication rate in this biopsy protocol was 1% (3 patients). Prostate cancer was detected in 118 of the 303 men (38. 9%). Overall this extensive protocol resulted in 6.6% improvement in the detection rate. Improvement was 6.5% in men with PSA 10 ng./ml. or less and 7% in those with PSA greater than 10 (not significant). CONCLUSIONS Increasing the number of biopsy cores and improving prostate peripheral zone sampling resulted in a significant improvement in the detection of prostate cancer.

Systematic biopsies accurately predict extracapsular extension of prostate cancer and persistent/recurrent detectable PSA after radical prostatectomy.

OBJECTIVES To determine if methodic analysis of systematic echo-guided biopsies associated with prostatic-specific antigen (PSA) and PSA density can accurately predict the actual pathologic stage of prostate cancer (Ca P). METHODS One hundred patients with clinically localized (T1, T2) Ca P who underwent radical prostatectomy (RP) were preoperatively staged by digital rectal examination (DRE), measurement of serum PSA (Yang Pros-check) and PSA density (PSAD), and transrectal echo-guided systematic biopsies (three in each lobe aiming to sample prostatic capsule) to evaluate T stage, Gleason grade, number of positive biopsies, and presence of cancer in the periprostatic tissues. Radical prostatectomy specimens were processed following the McNeal method. The PSA levels were measured every month for 2 years. RESULTS Extracapsular disease was detected on the specimen in 45% of the patients, persistent/recurrent detectable PSA in 47% (mean follow-up 18 months). Clinical stage T2 B, presence of Gleason grade 4, PSA > 25 ng/mL, PSAD > 0.6, number of positive biopsies > 66% of the total number of cores taken had a positive predictive value (PPV), respectively, of 72%, 66%, 80%, and 87%. Periprostatic tissue was evaluable on the core biopsies in 77% of the cases. Presence of cancer in the periprostatic fat on the core biopsies had a PPV of 94% for extracapsular disease/biological recurrence. CONCLUSIONS The presence of extracapsular cancerous tissue on prostatic core biopsies accurately predicts extracapsular extension of Ca P. Therefore, care should be taken when performing prostate biopsies to sample the prostate capsule and surrounding tissues to obtain a more accurate staging of the disease. The second best predictor of extracapsular disease is the percentage of positive biopsies.

Comparison of the BTA stat^ test with voided urine cytology and bladder wash cytology in the diagnosis and monitoring of bladder cancer

Objective: To compare the BTA statTM test (BTA stat), a new one-step immunochromatographic assay that can be performed in the urologist’s office or in the laboratory, to voided urine cytology and bladder wash cytology (cytology) in the diagnosis and monitoring of cancer of the bladder (BC). Methods: BTA stat and cytology were performed in a double-blinded, prospective, clinical study on specimens from 240 subjects (68 females; mean age of subjects: 64 years) suspected of having BC. Results: In 107 subjects with final diagnoses of BC confirmed by cystoscopy or cystoscopy and biopsy, the overall sensitivities of BTA stat and cytology were 65 and 33%, respectively. For tumor grades I, II, and III, the sensitivities of BTA stat were 39, 67 and 83%, respectively. Those of cytology were 4, 20 and 69%. Nine subjects had a diagnosis of ‘suspicious for bladder cancer’. The specificities of BTA stat and cytology in the 124 subjects without BC were 64 and 99%, respectively. In the subjects with a history of BC (n = 74), the specificities of BTA stat and cytology were 72 and 99%, respectively. The specificity of BTA stat was lower in subjects with benign or malignant genitourinary disease other than BC (46%) than in subjects without genitourinary disease (71%). Conclusions: The BTA stat test is considerably more sensitive than cytology in the detection of BC and can replace cytology as an adjunct to cystoscopy in the diagnosis and follow-up of patients with BC. However, due to low specificity, BTA stat should not be used without first ruling out potential interferences such as infections, renal disease and cancer, or genitourinary trauma.

Increased Immunodetection of Acidic Fibroblast Growth Factor in Bladder Cancer, Detectable in Urine

Acidic fibroblast growth factor is a regulatory peptide involved in cell proliferation, differentiation and motility. We used a polyclonal antiserum raised against purified native bovine acidic fibroblast growth factor, with no cross-reactivity for basic fibroblast growth factor to detect acidic fibroblast growth factor in tissue extracts and urine samples by means of a competitive enzyme immunoassay. Histochemical analysis was also performed on 10 specimens of normal urothelium and 50 of bladder cancer. Acidic fibroblast growth factor immunoreactive material was found in normal urothelium (1.77 +/- 2 ng./gm. tissue) and was increased more than 10-fold in patients with transitional cell carcinoma of the bladder (20.36 +/- 12 ng./gm. tissue). Immunohistochemical analysis localized immunoreactivity in the epithelial compartment of bladder tumors. Acidic fibroblast growth factor was assayed in urine from 579 individuals comprising a control group (114) and patients with benign prostatic hypertrophy (133), carcinoma of the prostate (96) or transitional cell carcinoma of the bladder (236). There was a significant difference in the frequency of urinary acidic fibroblast growth factor detection among the patients with invasive transitional cell carcinoma, the control group (p < 0.001) and the patients with prostatic disease (p < 0.01). The sensitivity was 72% and the specificity was 91%. Furthermore, the frequency of acidic fibroblast growth factor detection by enzyme immunoassay in the urine and the intensity of immunostaining was correlated with the stage of the disease. These data strongly suggest that acidic fibroblast growth factor is a potential marker for bladder tumors that may be of use in the noninvasive followup of patients with bladder cancer. We present a simple and reliable enzyme immunoassay for the detection of acidic fibroblast growth factor in voided urine that might be useful to quantitate this marker.

The management of stress urinary incontinence after radical prostatectomy

Up to 30% of patients complain about urine leakage after radical prostatectomy, but persistent stress incontinence (beyond 1 year) affects <5% of them. This complication is mainly caused by sphincter dysfunction. Some preventive measures have been described to decrease the risk of incontinence after radical prostatectomy, but with conflicting results. The effectiveness of preoperative and early postoperative physiotherapy is controversial. Moreover, while meticulous apical dissection of the prostate significantly improves postoperative continence, the benefit of other surgical techniques, e.g. preserving the bladder neck and the neurovascular bundles, is under debate. The treatment of persistent stress urinary incontinence is mainly based on surgery, as this type of incontinence usually does not respond to physiotherapy and anticholinergic medication. While injection therapy is safe and well tolerated, its effect on postoperative continence is limited and decreases with time. The best results are achieved by implanting an artificial urinary sphincter, but with significant complication and revision rates.

Complexed prostate-specific antigen, complexed prostate-specific antigen density of total and transition zone, complexed/total prostate-specific antigen ratio, free-to-total prostate-specific antigen ratio, density of total and transition zone prostate-specific antigen: results of the prospective multicenter European trial

This prospective, multicenter European Prostate Cancer Detection study evaluated the value and performance of the molecular forms of prostate-specific antigen (PSA) and their derivatives in combination with prostate gland and transition zone volumes in early detection of prostate cancer in patients with PSA levels between 4 and 10 ng/mL. Of 750 men enrolled at 7 different European urology centers into the study between November 2001 and March 2002, 340 (45.3%) had a total PSA (tPSA) between 4 and 10 ng/mL (age range, 46 to 87 years). In all patients, the ratio of complexed PSA (cPSA) to tPSA (c/tPSA), cPSA density (cPSAD), cPSAD of the transition zone, PSA, free PSA (fPSA), ratio of fPSA to tPSA (f/tPSA), tPSA density (PSAD), and PSAD of the transition zone were measured and collected 5 to 10 minutes before the sextant biopsy with 2 additional transition zone cores. Measurements of tPSA and fPSA were done with the AxSYM test, whereas cPSA was measured with the ACS 180 cPSA assay. All patients had a transrectal ultrasound-guided sextant prostate biopsy, and 2 additional transition zone biopsies and total and transition zone volumes were measured at the time of biopsy. Histopathologic findings revealed benign histology in 237 patients and prostate cancer in 103 patients (69.7% and 30.3%, respectively). Statistically significant differences included larger total volumes, larger transition zone volumes, and f/tPSA in patients with benign disease (P = 0.0009, P <0.0001, P <0.0001, respectively). At 90% and 95% sensitivity, specificity of cPSA was significantly greater than that for PSA (P <0.0001). At sensitivity levels of 90% and 95%, the specificity of the cPSA assay using cutoff values of 3.06 and 2.52 ng/mL was 20.3% and 9.1%, respectively. A cPSA cutoff value of 6.95 ng/mL and 7.57 ng/mL afforded 90% and 95% specificity for detecting prostate cancer. The area under the curve (AUC) in the receiver operating characteristics curve of cPSA was statistically significantly higher compared with tPSA (60.8 vs 56.9, P = 0.032). AUC for volume-related parameters PSAD, cPSAD, PSAD of the transition zone, and cPSAD of the transition zone were 62.8%, 63.1%, 63.0%, and 63.6%, respectively. cPSA performs better than tPSA in the differentiation between benign disease and prostate cancer and provides similar information to the f/tPSA ratio. In addition, cPSA and cPSA volume-related parameters (cPSAD, cPSAD of the transition zone) further improved the specificity of PSA in early detection of prostate cancer.

PAIN AND MORBIDITY OF AN EXTENSIVE PROSTATE 10-BIOPSY PROTOCOL: A PROSPECTIVE STUDY IN 289 PATIENTS

PURPOSE Some studies imply that increasing the number of prostate biopsy cores may improve the cancer detection rate. We performed a prospective study to evaluate pain and morbidity after an extensive transrectal ultrasound guided 10-core biopsy protocol. MATERIALS AND METHODS A total of 289 consecutive men with abnormal digital rectal examination findings and/or increased prostate specific antigen underwent extensive prostate biopsy involving 6 sextant and 4 peripheral biopsies. Each received an information leaflet a few days before the procedure. A single dose of fluoroquinolone and a rectal enema were administered before biopsy. In no case was the procedure performed using anesthesia. Immediately after biopsy patients were asked to complete a self-administered nonvalidated questionnaire evaluating the degree of pain and/or discomfort using a visual analog scale. In another questionnaire they listed the side effects noticed during month 1 after biopsy. RESULTS Although 48% of the 275 men who completed the initial questionnaire reported anxiety before the procedure, 78.8% of them were completely reassured by the information brochure. Of the 275 patients 47.6% described the procedure as painful, including only slightly painful (analog visual scale 3 or less) in 67.9%, while 33.8% described it as uncomfortable but not painful and 18.6% thought that it was neither painful nor uncomfortable. Of the 115 patients who engaged in sexual intercourse during month 1 after the procedure 78.3% noticed hematospermia an average of 10.9 days in duration. Of the 164 men who completed questionnaire 2, 74.4% noticed hematuria an average of 2.7 days in duration, 3.7% noticed pyrexia and 1.2% noticed acute prostatitis. In the 59 patients (36%) who reported delayed perineal pain it was slight in 64.4%, moderate in 30.5% and severe in 5.1%. No patient required hospitalization. CONCLUSIONS Although minor complications are common, the extensive 10-core prostate biopsy protocol is associated with few major complications. The occurrence and intensity of pain and discomfort are in the range reported after the standard 6-core biopsy protocol.

Percentage of Cancer on Biopsy Cores Accurately Predicts Extracapsular Extension and Biochemical Relapse after Radical Prostatectomy for T1–T2 Prostate Cancer

Purpose: To perform a multivariate analysis to investigate the usefulness of eight preoperative variables as predictors of final pathological stage (pT), positive surgical margins (PSM) and biological progression after radical prostatectomy (RP).Materials and Methods: In 143 patients undergoing RP for T1–T2 prostate cancer, the respective values of age, clinical stage, preoperative prostate–specific antigen (PSA), prostate–specific antigen density (PSAD), number of positive biopsies (NPB), Gleason score, length of tissue core invaded by cancer (LTI) and topography (uni/bilaterality) of positive biopsies for predicting extracapsular extension, PSM and biochemical failure (PSA≥0.05 ng/ml) were evaluated retrospectively. Univariate and multivariate analyses were applied to define the statistical significance of each variable. Actuarial survival without biological progression was calculated using the Kaplan–Meier method (log–rank test).Results: In this series, 44.8% of patients had extracapsular extension with 41.3% PSM. The mean PSA was 12.4 ng/ml. In univariate analysis, LTI (p<0.0001), NPB (p = 0.0023), PSA (p = 0.0039) and Gleason score (p = 0.0136) were the most powerful variables to predict pT stage; however, in logistic regression analysis, LTI was the most predictive feature. For prediction of PSM, some variables (LTI, NPB and PSA) were found to be of statistical value in univariate analysis, and LTI in combination with NPB and PSA in multivariate analysis. For biological progression, statistical analysis (log rank test) showed PSAD and LTI to be significant predictors.Conclusion: The pathological report regarding the biopsy contains crucial information influencing the prediction of pT stage, PSM and biological progression after RP. LTI, NPB and PSA are the most useful parameters for this purpose.

RADICAL PROSTATECTOMY FOR PROSTATE CANCER: THE PERINEAL APPROACH INCREASES THE RISK OF SURGICALLY INDUCED POSITIVE MARGINS AND CAPSULAR INCISIONS

PURPOSE We compare the incidence of positive surgical margins in patients who underwent perineal or retropubic radical prostatectomy for clinically localized (stage T1, T2) prostate cancer. MATERIALS AND METHODS In this retrospective, nonrandomized study we reexamined the specimens of 94 consecutive patients who underwent radical perineal (48) or retropubic (46) prostatectomy for clinically localized prostate cancer (stage T1, T2) and with pathological stage pT2 (intracapsular), pT3A (established extracapsular extension without positive margins) or pT3B (extracapsular extension with positive margins) without lymph node involvement (N0). We assessed the presence or absence of extracapsular cancer with or without positive margins, incisions of the prostatic capsule exposing cancer (surgically induced positive margins) or benign glandular tissue. Patients were followed for 3 to 66 months (mean 25) using an ultrasensitive prostate specific antigen assay with a lower detection limit of less than 0.05 ng./ml. RESULTS The overall incidence of positive margins in cancer tissue was 56% in the perineal and 61% in the retropubic group, and biochemical failure-free survival was 67% each. However, surgically induced positive margins in patients with organ confined disease were more frequent in the perineal than retropubic group (43 versus 29%, p < 0.05) and associated with a 37% risk of biochemical failure (prostate specific antigen greater than 0.1 ng./ml.) at mean followup. In addition, capsular incisions exposing benign tissue were more frequent in the perineal than retropubic group (90 versus 37%, p < 0.05) irrespective of pathological stage. CONCLUSIONS Although overall positive margins and biochemical failure rates are similar or identical for the perineal and retropubic approaches for organ confined prostate cancer, the perineal approach is associated with a significantly higher risk of capsular incisions and surgically induced positive margins and, thus, a higher risk of biochemical failure.