Deborah S. Smith

Measurement of prostate-specific antigen in serum as a screening test for prostate cancer

BACKGROUND Prostate-specific antigen (PSA) is secreted exclusively by prostatic epithelial cells, and its serum concentration is increased in men with prostatic disease, including cancer. We evaluated its usefulness in the detection and staging of prostate cancer. METHODS We measured serum PSA concentrations in 1653 healthy men 50 or more years old. Those with PSA values greater than or equal to 4.0 micrograms per liter then underwent rectal examination and prostatic ultrasonography. Ultrasound-directed prostatic needle biopsies were performed in the men with abnormal findings on rectal examination, ultrasonography, or both. The results were compared with those in 300 consecutively studied men 50 or more years old who underwent ultrasound-directed biopsy because of symptoms or abnormal findings on rectal examination. RESULTS Serum PSA levels ranged from 4.0 to 9.9 micrograms per liter in 6.5 percent of the 1653 men (107). Nineteen of the 85 men in this group (22 percent) who had prostatic biopsies had prostate cancer. Serum PSA levels were 10.0 micrograms per liter or higher in 1.8 percent of the 1653 men (30). Eighteen of the 27 men in this group (67 percent) who had prostatic biopsies had cancer. If rectal examination alone had been used to screen the men who had biopsies, 12 of the 37 cancers (32 percent) would have been missed. If ultrasonography alone had been used to screen these men, 16 of the 37 cancers (43 percent) would have been missed. Serum PSA measurement had the lowest error rate of the tests, and PSA measurement plus rectal examination had the lowest error rate of the two-test combinations. CONCLUSIONS The combination of measurement of the serum PSA concentration and rectal examination, with ultrasonography performed in patients with abnormal findings, provides a better method of detecting prostate cancer than rectal examination alone.

Potency, continence and complication rates in 1,870 consecutive radical retropubic prostatectomies.

PURPOSE We update results in a series of consecutive patients treated with anatomic radical retropubic prostatectomy regarding recovery of erections, urinary continence and postoperative complications. MATERIALS AND METHODS One surgeon performed anatomic radical retropubic prostatectomy on 1,870 men, using the nerve sparing modification when feasible. We evaluated recovery of erections and urinary continence in men followed for a minimum of 18 months. Patients who were not reliably potent before surgery, did not undergo a nerve sparing procedure, or received hormonal therapy or postoperative adjuvant radiotherapy were excluded from the analysis of potency rates but not of continence rates. Other postoperative complications were evaluated for the entire patient population. RESULTS Recovery of erections occurred in 68% of preoperatively potent men treated with bilateral (543 of 798) and 47% treated with unilateral (28 of 60) nerve sparing surgery. Recovery of erections was more likely with bilateral than with unilateral nerve sparing surgery in patients less than 70 years old (71 versus 48%, p<0.001) compared with patients with age 70 years old or older (48 versus 40%, p = 0.6). Recovery of urinary continence occurred in 92% (1,223 of 1,325 men) and was associated with younger age (p<0.0001) but not with tumor stage (p = 0.2) or nerve sparing surgery (p = 0.3). Postoperative complications occurred in 10% of patients overall and were associated with older age (p<0.002) but the incidence declined significantly with increasing experience of the surgeon (p<0.0001). There was no operative mortality. CONCLUSIONS Anatomic radical retropubic prostatectomy with the nerve sparing modification can be performed with favorable results in preserving potency and urinary continence. Better results are achieved in young men with organ confined cancer. Other complications can be reduced with increasing surgeon experience.

Serial Prostatic Biopsies in Men with Persistently Elevated Serum Prostate Specific Antigen Values

The objective of this study was to determine the need for repeat prostatic biopsies in men whose initial biopsy results revealed no evidence of cancer or atypia. We evaluated 1,136 men who underwent 1 or more prostatic biopsies in a longitudinal prostate specific antigen (PSA) based prostate cancer screening study that called for biopsy if the serum PSA level was greater than 4.0 ng./ml. (Hybritech assay) and findings on rectal examination or ultrasonography were abnormal or suspicious for cancer. Of the 1,136 men who underwent prostatic biopsy 391 (34%) had prostate cancer on the initial biopsy. Of 427 men who had negative initial biopsy results, a persistent serum PSA level of greater than 4.0 ng./ml. and abnormal rectal or ultrasound examination findings 82 (19%) had cancer on biopsy 2. Of 203 men with persistent abnormalities 16 (8%) had cancer on biopsy 3 and 6 of 91 (7%) had cancer on biopsy 4 or later. Thus, 96% of the cancers were detected through either biopsy 1 or 2. The median initial PSA level, followup PSA levels and the yearly rate of change in PSA were significantly greater in men whose cancer was detected compared with those of men whose cancer was not detected (6.4 versus 5.4 ng./ml., 7.4 versus 6.6 ng./ml. and 1.1 versus 0.7 ng./ml. per year, respectively). There was a trend for a higher percentage of tumors detected through serial screening to be pathologically organ confined with those detected through initial screening (73% versus 62%, p = 0.07). We conclude that men with a persistently elevated serum PSA value after an initial negative prostatic biopsy should routinely undergo at least 1 repeat biopsy to exclude adequately the presence of detectable prostate cancer.

5-Year Tumor Recurrence Rates After Anatomical Radical Retropubic Prostatectomy For Prostate Cancer

The new anatomical approach to radical retropubic prostatectomy with its nerve sparing option allows for preservation of erections, improved urinary continence, decreased blood loss, and lower operative mortality and morbidity rates. We sought to evaluate cancer control with this operation by determining the 5-year tumor recurrence rates using detectable serum prostate specific antigen levels as a criterion for tumor recurrence in a series of 925 consecutive men with clinical stage T1 or T2 prostate cancer. Overall, the 5-year probability of nonprogression was 78% (95% confidence limits 74 to 82%). The 5-year nonprogression rate was higher in patients whose tumors were not palpable (90% for impalpable tumors detected through transurethral resection of the prostate, 97% for impalpable prostate specific antigen detected tumors and 74% for palpable tumors). Nonprogression correlated with pathological tumor stage (91% for organ confined disease, 74% for positive margins or microscopic capsular perforation, 32% for seminal vesical invasion and virtually nil for lymph node metastases) and tumor grade (89% for well, 78% for moderately and 51% for poorly differentiated tumors). We conclude that anatomical radical prostatectomy achieves excellent cancer control for patients with organ confined prostate cancer.

Effect of Inflammation and Benign Prostatic Hyperplasia on Elevated Serum Prostate Specific Antigen Levels

PURPOSE We quantify the causes of elevated serum prostate specific antigen (PSA) concentrations in men whose prostate biopsies repeatedly showed no cancer. MATERIALS AND METHODS The effects of prostate volume, inflammation, echogenicity on ultrasound and calculi were examined in a large PSA-based screening population of 148 men with serum PSA concentrations greater than 4.0 ng./ml., findings suspicious for cancer on digital rectal examination and multiple negative biopsies. These men were selected and compared to 64 men with suspicious rectal examinations, multiple negative biopsies and serum PSA concentrations of 4.0 ng./ml. or less. RESULTS The high PSA group had larger prostates (68 versus 33 cc, p = 0.0001) and significantly more subclinical prostatic inflammation. Acute and chronic inflammation was more prevalent in the high PSA group (63% versus 27%, p = 0.0001 and 99% versus 77%, p = 0.0001, respectively). A simultaneous regression analysis showed that prostatic size accounted for 23%, inflammation 7%, prostatic calculi 3% and nonisoechoic ultrasound lesions 1% of the serum PSA variance. CONCLUSIONS Prostate volume and inflammation are the most important factors contributing to serum PSA elevation in men without clinically detectable prostate cancer.

CANCER RECURRENCE AND SURVIVAL RATES AFTER ANATOMIC RADICAL RETROPUBIC PROSTATECTOMY FOR PROSTATE CANCER: INTERMEDIATE-TERM RESULTS

PURPOSE We evaluate cancer recurrence and survival rates following anatomic radical retropubic prostatectomy. MATERIALS AND METHODS From 1983 through August 1997, 1 surgeon performed anatomic radical retropubic prostatectomy in 1,778 men (mean age plus or minus standard deviation 63+/-7), using a unilateral or bilateral nerve sparing modification when feasible (93%). Postoperative adjuvant radiation therapy (mean dose 60 Gy.) was given to 4% of patients because of adverse pathological findings. Patients were followed with semiannual prostate specific antigen (PSA) tests and annual digital rectal examinations. Followup PSA 0.3 ng./ml. or greater was considered evidence of cancer recurrence. We used Kaplan-Meier product limit estimates to calculate 7-year cancer recurrence-free probabilities, prostate cancer specific survival and all cause survival (overall, and stratified by age, preoperative PSA, tumor grade and tumor stage). We used multivariate Cox proportional hazards models to determine clinical and pathological parameters that provided unique predictive information about cancer recurrence. RESULTS The 7-year recurrence-free survival was significantly associated with lower preoperative PSA (estimated probability of nonprogression 76 to 93% for PSA less than 10), nonpalpable, localized clinical stage (79%), lower tumor grade (84 and 68% for well and moderately differentiated, respectively) and localized pathological stage (81% for pT1 or pT2) (all log rank test p <0.0001) but not age at surgery. All predictors except clinical stage and age remained significant within the multivariate model. Controlling for all other predictors, adjuvant radiation therapy in patients with unfavorable pathology was significantly associated with better recurrence-free survival (p=0.02). The estimated 7-year prostate cancer specific survival rate was 97% and the all cause survival rate was 90%. Cancer specific and all cause survival were significantly associated with lower grade and localized pathological stage (p <0.0001). CONCLUSIONS Anatomic radical retropubic prostatectomy with the nerve sparing modification can be performed with good cancer control.

LOWER CALICEAL STONE CLEARANCE AFTER SHOCK WAVE LITHOTRIPSY OR URETEROSCOPY: THE IMPACT OF LOWER POLE RADIOGRAPHIC ANATOMY

PURPOSE We determine whether there is a significant relationship between the spatial anatomy of the lower pole, as seen on preoperative excretory urography (IVP), and the outcome after shock wave lithotripsy or ureteroscopy for a solitary lower pole caliceal stone 15 mm. or less. MATERIALS AND METHODS Between January 1992 and June 1996, 34 patients with 15 mm. or less solitary lower pole stone underwent ureteroscopy with intracorporeal lithotripsy (13) or extracorporeal shock wave lithotripsy (ESWL) with a Dornier HM3 lithotriptor (21). On pretreatment IVP lower pole infundibular length and width, infundibulopelvic angle of the stone bearing calix were measured. Stone size and area were determined from an abdominal plain x-ray. A plain x-ray of the kidneys, ureters and bladder was obtained in all patients at a median followup of 12.3 and 8 months in the ureteroscopy and ESWL groups, respectively. RESULTS After initial therapy the overall stone-free rate was 62 and 52% in the ureteroscopy and ESWL groups, respectively. Stone-free status after ESWL was significantly related to each anatomical measurement. Infundibulopelvic angle 90 degrees or greater, and infundibular length less than 3 cm. and width greater than 5 mm. were each noted to correlate with an improved stone-free rate after ESWL. In contrast, the stone-free rate after ureteroscopy was not statistically significantly impacted by these anatomical features, although a clinical stone-free trend was identified relating to a favorable infundibular length and infundibulopelvic angle. The infundibulopelvic angle was 90 degrees or greater in 4 stone-free patients (12% overall), including 2 who underwent ureteroscopy and 2 who underwent ESWL. On the other hand, in 2 and 4 stone-free patients (18% overall) who underwent ureteroscopy and ESWL, respectively, favorable radiographic features consisted of a short, wide but acutely angulated infundibulum with the infundibulopelvic angle less than 90 degrees, and infundibular length less than 3 cm. and width 5 mm. or greater. In contrast, in 4 and 6 patients (29% overall) who underwent ureteroscopy and ESWL, respectively, all 3 radiographic features were unfavorable with the infundibulopelvic angle less than 90 degrees, and infundibular length greater than 3 cm. and width less than 5 mm. In these cases the stone-free rate was 50 and 17% after ureteroscopy and ESWL, respectively. CONCLUSIONS The 3 major radiographic features of the lower pole calix (infundibulopelvic angle, and infundibular length and width) can be easily measured on standard IVP using a ruler and protractor. Each factor individually has a statistically significant influence on stone clearance after ESWL. A wide infundibulopelvic angle or short infundibular length and broad infundibular width regardless of infundibulopelvic angle are significant favorable factors for stone clearance following ESWL. Conversely, these factors have a cumulatively negative effect on the stone clearance rate after ESWL when they are all unfavorable. In ureteroscopy spatial anatomy has less of a role in regard to stone clearance but it may have a negative impact when there is uniformly unfavorable anatomy.

Artificial neural networks in the diagnosis and prognosis of prostate cancer: a pilot study.

There is controversy about how prostate cancer screening tests should best be used because of the false-negative and false-positive results. There also is controversy about prostate cancer treatment because of errors in tumor staging, uncertainty about treatment efficacy and the variable natural history of the disease. We sought to determine in a pilot study whether artificial neural networks would be helpful to predict biopsy results in men with abnormal screening test(s) and to predict treatment outcome after radical prostatectomy. To predict biopsy results, we extracted data from a prostate specific antigen (PSA) based screening study data base in 1,787 men with a serum PSA concentration of more than 4.0 ng./ml. (approximately 40% of the men also had suspicious findings on digital rectal examination). To predict cancer recurrence after radical prostatectomy, we extracted data from a random sample of 240 patients selected from a data base of men who had undergone radical prostatectomy. The neural network predicted the biopsy result with 87% overall accuracy, and its output threshold could be adjusted to achieve the desired tradeoff between sensitivity and specificity. It also predicted tumor recurrence with 90% overall accuracy. We conclude that trained neural networks may be useful in decision making for prostate cancer patients.

The Nature of Prostate Cancer Detected Through Prostate Specific Antigen Based Screening

Prostate specific antigen (PSA) based screening nearly doubles the detection rate of early prostate cancer. However, it is unknown whether the additional tumors detected are medically important. Traditional clinical and pathological features associated with medically important cancer include a palpable tumor, multifocal or diffuse involvement and moderately or poorly differentiated histology. In contrast, microfocal, well differentiated tumors are considered to be possibly medically unimportant. We sought to examine the clinical and pathological tumor stage and tumor grade in 1,169 consecutive men whose prostate cancer was detected during serial PSA based screening protocols involving 24,346 men screened at 6-month intervals. Of the patients 97% had clinically localized (clinical stage T1 or T2) tumors, of which 39% were not palpable (stage T1). Of the men whose cancer was detected through initial screening who underwent surgical staging 69% had pathologically organ confined (pathological stage whose cancer was detected through initial screening pT1 or pT2) disease compared to 74% whose cancer was detected through serial screening (after an initially negative screening). Impalpable, clinically focal, well differentiated minimal tumors were noted in 16% of the men. However, only 3% of the men who underwent surgical staging had impalpable, pathologically microfocal, well differentiated minimal tumors. We conclude that the majority of tumors detected through PSA based screening have the clinical and pathological features associated with medically important prostate cancer.

Interexaminer variability of digital rectal examination in detecting prostate cancer

OBJECTIVES Digital rectal examination (DRE) is an important method of prostate cancer detection used by primary care physicians and medical specialists to identify patients in whom a prostatic biopsy is warranted. However, there is little empirical evidence assessing the degree of interexaminer variability in the use of DRE for the detection of prostate cancer. We addressed this issue within the framework of a prostate cancer screening study. METHODS We performed DRE examinations in 116 consecutive volunteers twice on the same day, with different urologists performing the examinations. The urologists were blinded to the results of the other examination and to the subjects serum prostate-specific antigen (PSA) level. DRE results were coded as being benign or sufficiently suspicious for cancer to warrant a prostatic biopsy. RESULTS Examiners independently agreed on the DRE findings in 98 of the 116 (84%) subjects. However, when adjusted for chance agreement, the interexaminer agreement among urologists was only fair (ie, kappa = 0.22, P = 0.009). Interexaminer variability was greater between faculty and resident examiners than among faculty examiners. CONCLUSIONS Our results suggest that the reproducibility of DRE for detecting prostate cancer is only fair among urologists. Further studies are indicated to evaluate interexaminer variability between primary care physicians and urologists.