Predictive Value of Four Kallikrein Markers for Pathologically Insignificant Compared With Aggressive Prostate Cancer in Radical Prostatectomy Specimens: Results From the European Randomized Study of Screening for Prostate Cancer Section Rotterdam

Background

Treatment decisions can be difficult in men with low-risk prostate cancer (PCa).

Objective

To evaluate the ability of a panel of four kallikrein markers in blood—total prostate-specific antigen (PSA), free PSA, intact PSA, and kallikrein-related peptidase 2—to distinguish between pathologically insignificant and aggressive disease on pathologic examination of radical prostatectomy (RP) specimens as well as to calculate the number of avoidable surgeries.

Design, setting, and participants

The cohort comprised 392 screened men participating in rounds 1 and 2 of the Rotterdam arm of the European Randomized Study of Screening for Prostate Cancer. Patients were diagnosed with PCa because of an elevated PSA ≥3.0 ng/ml and were treated with RP between 1994 and 2004.

Outcome measurements and statistical analysis

We calculated the accuracy (area under the curve [AUC]) of statistical models to predict pathologically aggressive PCa (pT3–T4, extracapsular extension, tumor volume >0.5 cm³, or any Gleason grade ≥4) based on clinical predictors (age, stage, PSA, biopsy findings) with and without levels of four kallikrein markers in blood.

Results and limitations

A total of 261 patients (67%) had significant disease on pathologic evaluation of the RP specimen. While the clinical model had good accuracy in predicting aggressive disease, reflected in a corrected AUC of 0.81, the four kallikrein markers enhanced the base model, with an AUC of 0.84 (p < 0.0005). The model retained its ability in patients with low-risk and very-low-risk disease and in comparison with the Steyerberg nomogram, a published prediction model. Clinical application of the model incorporating the kallikrein markers would reduce rates of surgery by 135 of 1000 patients overall and 110 of 334 patients with pathologically insignificant disease. A limitation of the present study is that clinicians may be hesitant to make recommendations against active treatment on the basis of a statistical model.

Conclusions

Our study provided proof of principle that predictions based on levels of four kallikrein markers in blood distinguish between pathologically insignificant and aggressive disease after RP with good accuracy. In the future, clinical use of the model could potentially reduce rates of immediate unnecessary active treatment.     

Radical cystectomy in septuagenarian patients with bladder cancer

Introduction: Clinical results of radical cystectomy performed on elderly bladder cancer patients over 70 years old were assessed to determine whether age is one of the critical points for the application of this type of surgery. Materials: From January 1992 to December 2002, 41 radical cystectomy performed in septuagenarian population were compared with 197 performed in patients less than 70 years of age. Results: The early and late complication rate for septuagenarians was 29.7% and 12%, compared with 26.9% and 9.6% for patients younger than 70 years respectively. The overall mortality rate for septuagenarians was 4.9%, compared with 8.6% for patients younger than 70 years. There was no significant difference between the two groups with regard to pathologic stage or length of hospital stay. The 5-year overall survival rate for septuagenarians was 53% compared with 59% for patients younger than 70 years. Conclusions: When indicated after adequate preoperative assessment and optimization of the patient, radical cystectomy is a safe procedure in the septuagenarians and patient should not be denied surgery dependent on chronologic age.     

The role of complete surgical resection in stage IV neuroblastoma

The purpose of this study was to examine the outcome of attempted radical surgical resection in patients with stage IV neuroblastoma. Between 1989 and 2003, 20 (median age 2.4 years, range 0.5–8.7 years) children with stage IV neuroblastoma were treated at the Department of Pediatrics. Surgery was performed in 7 consecutive children (6 male and 1 female) between July 1997 and February 2002 at the Department of Urology in Bonn. Mean age at diagnosis was 57 months (21–104 months). Mean age at the time of surgery was 54 months (8–390 months). Follow-up was available for all patients (100%) and mean follow-up after the operation was 32.5 months (4–56 months). Primary localization of the tumor was retroperitoneal in all cases; 4 out of 7 patients (57%) also had additional adrenal, 3 out of 7 (42%) paraganglion and 1 out of 7 (14%) thoracic primaries. Bone marrow and lymph node metastases were found in all patients (100%). Surgery led to complete tumor resection in 6 out of 7 patients (85%). Surgical approach was abdominal (chevron incision) in 6 out of 7 (85%) of the patients, in one patient the approach was thoraco-abdominal. After induction chemotherapy and delayed surgery, 6 out of 7 (86%) patients showed a complete remission (CR) and the mean CR lasted for about 27.7 months (range 3.1–55.4 months). At the last time of follow-up 5 out of 7 (71%) patients were alive, 2 had died due to recurrent disease. Mean time to recurrent disease was 24 and 51 months, respectively. Mean overall survival time since diagnosis was 38.3 months (11–64 months) and mean event-free survival was 34.5 months (11–60.3 months). The final outcome, overall survival and event-free survival time was influenced by metastatic or local relapse. Tumor resection is beneficial but the value of surgery can only be judged when we are able to control metastatic disease in stage IV neuroblastoma. The final outcome may rely on the extent of complete surgical resection, but is also related to treatment of metastases. A longer follow-up period is indicated to detect long term outcome.     

An evaluation of the decreasing incidence of positive surgical margins in a large retropubic prostatectomy series

PURPOSE: Positive surgical margins adversely affect biochemical recurrence-free survival after radical retropubic prostatectomy (RRP) for prostate cancer. We retrospectively reviewed a large series of men who underwent RRP at a single academic university urology program to define the change in the incidence of organ confined (OC) disease and positive surgical margin (SM+) during the last 2 decades. MATERIALS AND METHODS: Between 1982 and 2001, 9,035 men underwent RRP for clinically localized prostate cancer (T1 to T3a) at a single institution. We compared the incidences of OC disease and SM+ in this population. RESULTS: An increasing proportion of men presented with OC disease over time. The incidence of SM+ in the overall RRP population decreased dramatically over time. However, in men with nonorgan confined disease (pT3), the proportion with SM+ was stable and consistently elevated (22.7% to 27.8%), after the initial decrease from the early 1980s (53%). CONCLUSIONS: Widespread early detection programs for prostate cancer resulted in a downward stage migration in men presenting with clinically localized prostate cancer at our institution during the last 2 decades. The decrease in the percentage of men with SM+ was due to the increasing number of men with organ confined disease. These results imply that the decrease in surgical margin rates in the overall RRP population is most likely due to stage migration and improved patient selection, rather than major improvements in surgical technique. The stable percentage of SM+ among men with pT3 disease dictates the need for continued evaluation of surgical technique and the need for effective adjuvant therapy.     

Retrospective study on stage B prostate cancer in the Hokuriku District, Japan

BACKGROUND: The present study was conducted to investigate how patients with clinically localized prostate cancer were treated in the Hokuriku District, Japan. METHODS: Medical records of 536 patients with stage B prostate cancer were retrospectively reviewed. The patients were diagnosed and treated at four university hospitals and 32 collaborating hospitals in the Hokuriku District. RESULTS: Because their medical records were incomplete and/or they not available for follow up, 79 cases were excluded from this study. Conservative treatment with hormone therapy was used for 248 cases. Radical prostatectomy was performed in 199 cases, only 27 of whom underwent surgical monotherapy. There was no significant difference in disease-specific survival rates between the hormone (69.0%) and surgery group (83.2%) after 110 months. Results of the analysis of disease-specific survival rates according to histologic grade showed that patients with poorly differentiated cancers treated with hormone therapy were the only subset with significant differences when compared against the other patients. CONCLUSION: The value of prostatectomy alone or added was marginal in terms of survival. Only patients with poorly differentiated cancer might benefit from prostatectomy.     

The male perineal sling: comparison of sling materials

PURPOSE: Urinary incontinence continues to be a significant problem for patients after radical prostatectomy. The male perineal sling is emerging as a safe and effective treatment option for postprostatectomy stress urinary incontinence. We compare the efficacy of porcine dermal collagen and silicone mesh as the sling material. MATERIALS AND METHODS: Of 36 patients with postprostatectomy stress urinary incontinence a porcine dermal collagen sling was placed in 20 and a silicone mesh sling was placed in 16. The sling was placed at the bulbar urethra and secured to 3 titanium bone screws anchored into the medial aspect of bilateral inferior pubic rami. RESULTS: Results at 12 months were compared. In the dermis group 9 (56%) patients were cured of incontinence (no pads daily), 5 (31%) had significant improvement (decrease of 50% or more in pads daily) and 2 (13%) had no change in symptoms. In the silicone mesh group 14 (87%) patients were cured of incontinence and 2 (13%) were significantly improved. Results showed that a previously placed artificial urinary sphincter led to poorer outcomes but a history of radiation therapy did not affect results. The most common complication was temporary urinary retention observed in 1 (5%) patient in the dermis group and 2 (12%) in the silicone mesh group. CONCLUSIONS: Early results demonstrate that the male sling is a safe and efficacious treatment option for postprostatectomy urinary incontinence. This study demonstrates superior outcomes with the synthetic silicone mesh sling compared to the porcine dermal collagen.     

Radionuclide bone scintigraphy in patients with biochemical recurrence after radical prostatectomy: when is it indicated?

OBJECTIVE: To evaluate the use of radionuclide bone scintigraphy following biochemical recurrence after radical retropubic prostatectomy (RRP) for localized prostate cancer. PATIENTS AND METHODS: Of 1197 patients undergoing RRP we identified those with biochemical recurrence and who had also had a bone scan. Biochemical recurrence was defined as a prostate specific antigen (PSA) level of > or = 0.4 ng/mL. Patients with indeterminate bone scan findings and those in whom the interval between the PSA test and the bone scan was >3 months were excluded. Patient age, PSA level and other relevant pathological details were recorded. Clinical symptoms at the time of bone scan, androgen deprivation after RRP, bone scintigram details and time to recurrence were documented. RESULTS: Of the 1197 patients, 153 (12.8%) had a biochemical recurrence and 35 (23%) of these had a total of 44 bone scans taken over a mean (sd) follow-up of 70.4 (35.6) months; 34 (77%) bone scans were negative (group 1) and 10 (33%) positive (group 2). In group 1 the mean PSA at the bone scan was 5.2 ng/mL; 76% of the patients had a PSA of < 7 ng/mL. In group 2 the mean PSA at the bone scan was 30.7 ng/mL and all patients had a PSA of >7 ng/mL. The only significant difference between the groups was the PSA at the time of the bone scan (P < 0.001). CONCLUSION: Bone scintigraphy is a sensitive diagnostic tool for detecting prostate cancer metastases to bone. A bone scan in patients with a serum PSA of <7 ng/mL on biochemical recurrence after RRP is unlikely to be positive, whereas a PSA of > or = 20 ng/mL is. The presence of skeletal symptoms or a PSA level of >7 ng/mL should prompt the clinician to obtain a bone scintigram.     

Bulbourethral composite suspension:: a new operative technique for post-prostatectomy incontinence

PURPOSE: A new bulbourethral sling procedure is proposed for patients with post-radical prostatectomy incontinence. MATERIAL AND METHODS: Bulbourethral composite suspension was performed in 16 consecutive patients, of whom 6 (38%) had severe stress incontinence and depended on a condom urinal catheter. Urinary stress incontinence was assessed preoperatively by a modified pad test, urethrocystoscopy and urodynamic evaluation. The procedure was performed with a longitudinal perineal and a transverse suprapubic incision with the patient under regional anesthesia. We placed a porcine dermis for urethral protection and a polypropylene retropubic sling, which was tied suprapubically with the patient coughing and during retrograde urethral closure pressure monitoring at 60 cm H2O. RESULTS: Preoperative evaluation excluded detrusor instability and urethral stricture. The polypropylene band was placed without neurogenic or vascular complications. All patients had primary wound healing. Patients reported only minimal postoperative pain. Clinical followup was performed a median of 14 months postoperatively (range 6 to 32). Of the 16 patients 11 (69%) were completely dry and 1 (6%) reported improved continence, while 4 (25%) had no benefit, including 2 who underwent an artificial sphincter procedure. Preoperative mean daily pad use decreased from 7 (range 2 to 12) to 1 (range 0 to 10) postoperatively (p = 0.0004) and postoperative quality of life improved significantly (p <0.0001). CONCLUSIONS: Bulbourethral composite suspension is a new, efficient operative sling technique in patients with severe post-prostatectomy stress urinary continence. Because morbidity and complications are low, this new technique may become an alternative to artificial urinary sphincter implantation. Long-term observation of urethral and detrusor function is necessary to elucidate the specific contribution of bulbourethral composite suspension in restoring urinary continence after radical prostatectomy.     

Endocrine therapy with or without radical prostatectomy for T1b-T3N0M0 prostate cancer

BACKGROUND: We retrospectively compared the 5-year survival rates of T1b-T3N0M0 prostate cancer patients treated either by endocrine therapy plus radical prostatectomy or endocrine therapy alone. METHODS: Clinical T1b-T3N0M0 prostate cancer patients were enrolled at 104 institutions in Japan. They were assigned to study 1 (n = 176), if they were indicated to prostatectomy, if not indicated, they were assigned to study 2 (n = 151). The indication of prostatectomy was based on the clinical judgement of physicians and/or patients. Those assigned to study 1 underwent prostatectomy and adjuvant endocrine therapy with or without preoperative androgen deprivation. Those assigned to study 2 were treated with leuprorelin acetate with or without chlormadinone acetate. They were followed-up every 3 months until death or for 5 years and over. RESULTS: Those assigned to study 1 were younger (mean age 67.2 vs 75.7 years), less advanced in clinical stage, and had lower prostate specific antigen levels (mean 43.8 vs 103.6 ng/mL). Death for any reason was observed less frequently in study 1 (n = 29, 16%) than study 2 (n = 50, 33%), and the 5-year overall survival rate was higher in study 1 (87 vs. 68%). However, prostate cancer deaths were comparatively seldom (9% in study 1 and 7% in study 2), resulting in the identical 5-year cause specific survival rate in both study groups (91%). In both study groups the overall survival was almost equal to the natural survival of age-matched men. CONCLUSIONS: Endocrine therapy offers a reasonable survival rate in T1b-T3 prostate cancer patients within a 5-year follow-up. Observation will be extended to determine 10-year outcomes.     

Radical prostatectomy and adjuvant endocrine therapy for prostate cancer with or without preoperative androgen deprivation: Five-year results

BACKGROUND: The effects of preoperative androgen deprivation on the outcomes of prostate cancer patients who received radical prostatectomy and subsequent adjuvant endocrine therapy have not yet been fully evaluated. METHODS: Patients with stage A(2), B or C prostate cancers were randomized to one of two groups: group I (n = 90), who received androgen deprivation (leuprolide and chlormadinone acetate) for 3 months followed by radical prostatectomy and subsequent adjuvant endocrine therapy (leuprolide alone), and group II (n = 86), who underwent the surgery followed by 3-month androgen deprivation (leuprolide and chlormadinone acetate) and subsequent adjuvant endocrine therapy (leuprolide alone). The effects of preoperative androgen deprivation on survival, clinical relapse (serum prostate specific antigen, PSA, above the normal level, local recurrence, or distant metastases), and PSA relapse (PSA above the detectable level) were evaluated at 5 years or later after treatment. RESULTS: There were no significant differences in overall, cause-specific, clinical relapse-free, or PSA relapse-free survival rates between the two groups. In a subanalysis, no prostate cancer deaths or clinical relapses were noted in 29 patients with organ-confined disease (OCD: negativity of capsular invasion, seminal vesicle invasion, surgical margins or nodal involvement). The odds ratio for OCD depending on group assignment was 2.44 (95% confidence interval, CI 1.04-5.72), for group I, demonstrating a higher probability of having OCD. This ratio was increased to 4.00 (95% CI 1.06-15.16) if the analysis was conducted in a subpopulation with prostate specific antigen levels less than 35.6 ng/mL and with clinical stage B or C cancers. CONCLUSION: Preoperative androgen deprivation has no demonstrable benefit in 5-year outcomes for patients undergoing radical prostatectomy and adjuvant endocrine therapy. However, it did increase the probability of OCD, which was associated with no clinical relapse during the follow-up. A longer observation is needed to clarify the exact extent of the benefits in terms of survival.