Bruce L. Dalkin

Comparison of Digital Rectal Examination and Serum Prostate Specific Antigen in the Early Detection of Prostate Cancer: Results of a Multicenter Clinical Trial of 6,630 Men

&NA; To compare the efficacy of digital rectal examination and serum prostate specific antigen (PSA) in the early detection of prostate cancer, we conducted a prospective clinical trial at 6 university centers of 6,630 male volunteers 50 years old or older who underwent PSA determination (Hybritech Tandom‐E or Tandem‐R assays) and digital rectal examination. Quadrant biopsies were performed if the PSA level was greater than 4 &mgr;g./l. or digital rectal examination was suspicious, even if transrectal ultrasonography revealed no areas suspicious for cancer. The results showed that 15% of the men had a PSA level of greater than 4 &mgr;g./l., 15% had a suspicious digital rectal examination and 26% had suspicious findings on either or both tests. Of 1,167 biopsies performed cancer was detected in 264. PSA detected significantly more tumors (82%, 216 of 264 cancers) than digital rectal examination (55%, 146 of 264, p = 0.001). The cancer detection rate was 3.2% for digital rectal examination, 4.6% for PSA and 5.8% for the 2 methods combined. Positive predictive value was 32% for PSA and 21% for digital rectal examination. Of 160 patients who underwent radical prostatectomy and pathological staging 114 (71%) had organ confined cancer: PSA detected 85 (75%) and digital rectal examination detected 64 (56%, p = 0.003). Use of the 2 methods in combination increased detection of organ confined disease by 78% (50 of 64 cases) over digital rectal examination alone. If the performance of a biopsy would have required suspicious transrectal ultrasonography findings, nearly 40% of the tumors would have been missed. We conclude that the use of PSA in conjunction with digital rectal examination enhances early prostate cancer detection. Prostatic biopsy should be considered if either the PSA level is greater than 4 &mgr;g./l. or digital rectal examination is suspicious for cancer, even in the absence of abnormal transrectal ultrasonography findings.

Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial

To present the results (to January 1996, the end of blinded treatment) of the Nutritional Prevention of Cancer (NPC) Trial, a randomized trial of selenium (200 µg daily) designed to test the hypothesis that selenium supplementation (SS) could reduce the risk of recurrent nonmelanoma skin cancer among 1312 residents of the Eastern USA.

Selection of optimal prostate specific antigen cutoffs for early detection of prostate cancer: receiver operating characteristic curves.

A prospective clinical trial of prostate cancer screening was conducted at 6 university centers including 6,630 men 50 years old or older who underwent a serum prostate specific antigen (PSA) determination and digital rectal examination. Biopsies were performed if the PSA level was greater than 4.0 ng./ml. (Hybritech Tandem assay) or digital rectal examination was suspicious for cancer. We evaluated the effect on biopsy rate and cancer detection if the cutoff value was shifted from 4.0 to age-specific reference ranges recommended in the literature. In men 50 to 59 years old with normal digital rectal examination findings a decrease from 4.0 to 3.5 ng./ml. would have resulted in a 45% increase in the number of biopsies (39 of 87) and a projected 15% increase in cancer detection. An increase from 4.0 to 4.5 ng./ml. in men 60 to 69 years old would result in 15% fewer biopsies (35 of 238) and would miss 8% of the organ confined tumors (2 of 25). Increasing the cutoff to 6.5 ng./ml. in men 70 years old or older would result in 44% fewer biopsies (70 of 159) and would miss 47% of the organ confined cancers (7 of 15). The number of biopsies performed for each cancer detected with a PSA level of greater than 4.0 ng./ml. remains constant across age groupings, which suggests that the cutoff of 4.0 ng./ml. does not need to be altered in the older men, since it is apparently unaffected by the simultaneously increasing prevalence of benign prostatic hyperplasia and cancer with age. We conclude that a serum PSA concentration of 4.0 ng./ml. should be used as a general guideline for biopsy in all age groups.

Comparison of Prostate Specific Antigen Concentration Versus Prostate Specific Antigen Density in the Early Detection of Prostate Cancer: Receiver Operating Characteristic Curves

We present the results of a prospective multicenter clinical trial of nearly 5,000 men in which prostate specific antigen (PSA) density was compared to the serum PSA concentration alone for early detection of prostate cancer. All men were evaluated with PSA and digital rectal examination. If PSA was elevated (greater than 4 ng./ml., Hybritech Tandem assay) or digital rectal examination was suspicious, transrectal ultrasound guided biopsies were recommended. Prostate volume was estimated by transrectal ultrasound measurements using a prolate ellipse volume calculation and PSA density was calculated by dividing serum PSA concentration by gland volume. Using a PSA density cutoff of 0.15 as recommended in the literature enhanced specificity but at the cost of missing half of the tumors. Of the organ confined neoplasms 47% were detected by a PSA of greater than 4.0 ng./ml. but they were missed by a PSA density of more than 0.15. PSA density may not be predictive for cancer because accurate estimation of transrectal ultrasound volume is difficult (r = 0.61 for estimated transrectal ultrasound volume versus pathological prostate weight). However, a relationship does exist among transrectal ultrasound volume, PSA and positive predictive value for cancer. PSA concentrations of less than 4.0 ng./ml. did not indicate a need for biopsy (positive predictive value 12 to 17%) unless the digital rectal examination findings were suspicious for cancer. A high percentage of patients with a PSA of more than 10 ng./ml. had cancer (30 to 75%), regardless of gland size. Patients with intermediate PSA concentrations (4.1 to 9.9 ng./ml.) and a gland size of 50 cc or less had a 35 to 51% positive predictive value, while those with intermediate PSA concentrations and a large gland (more than 50 cc) had a 15% positive predictive value. We conclude that in men with a PSA level of 4.1 to 9.9 ng./ml., and normal digital rectal examination and transrectal ultrasound findings, the use of a PSA density cutoff of more than 0.15 for biopsy results in half of the tumors being missed. Thus, we recommend that men in this group undergo biopsy based upon serum PSA concentration rather than PSA density.

EFFECT OF PATIENT AGE ON EARLY DETECTION OF PROSTATE CANCER WITH SERUM PROSTATE-SPECIFIC ANTIGEN AND DIGITAL RECTAL EXAMINATION *

This study was designed to determine the effects of age by decade on the efficacy of digital rectal examination (DRE) and serum prostate-specific antigen (PSA) for early detection of prostate cancer in men aged fifty and over. A prospective multicenter clinical trial was conducted at six university centers. All 6,630 male volunteers underwent a serum PSA (Hybritech, Tandem) determination and DRE. Quadrant biopsies of the prostate were performed if PSA was > 4 ng/mL or DRE suspicious. A total of 1,167 biopsies were performed, and 264 cancers were detected. The cancer detection rate increased from 3 percent in men aged fifty to fifty-nine to 14 percent in men eighty years or older (p < 0.0001). PSA detected significantly more of the total cancers than DRE at all age ranges (p < 0.05). The positive predictive values (PPV) for PSA were 32 percent (50-59 years), 30 percent (60-69 years), 34 percent (70-79 years), and 38 percent (80+ years). The corresponding PPVs for DRE were 17 percent, 21 percent, 25 percent, and 38 percent. Eighteen percent of the cancers were detected solely by DRE, whereas 45 percent of cancers were detected solely by PSA. Thus, the use of both tests in combination provided the highest rate of detection in all age groups. One hundred-sixty patients underwent radical prostatectomy and pathologic staging. Cancer was organ-confined in 74 percent (25/34) of men aged fifty to fifty-nine, 76 percent (65/86) of men aged sixty to sixty-nine, and 60 percent (24/40) of men aged seventy or over (chi 2, < 70 vs. > or = 70, p < 0.05). Early detection programs yield a lower, yet still substantial, cancer detection rate in younger men, and there is a greater likelihood for detection of organ-confined disease in this age range. Younger men have the longest projected life expectancy and, therefore, the most to gain from early prostate cancer detection.

Positive Surgical Margins at Radical Prostatectomy Predict Prostate Cancer Specific Mortality

PURPOSE Positive surgical margins in men undergoing radical prostatectomy for prostate cancer are associated with an increased risk of biochemical recurrence. Few data are available on the role of positive surgical margins in prostate cancer specific mortality. Using a large, population based national cancer registry we evaluated the risk of prostate cancer specific mortality associated with margin status. MATERIALS AND METHODS The SEER cancer registry data for patients diagnosed between 1998 and 2006 were used to identify men undergoing radical prostatectomy for prostate cancer. Margin status, pathological stage, Gleason grade and postoperative radiation therapy were recorded along with demographic data. Multivariate Cox regression analysis was used to estimate the risk of prostate cancer specific mortality associated with positive surgical margins. RESULTS A total of 65,633 patients comprised the cohort in which 291 (0.44%) prostate cancer specific deaths occurred during an average followup of 50 months. Positive surgical margins were reported in 21.2% of cases and were more common in pT3a than pT2 tumors (44% vs 18%, p <0.001) and higher grade tumors (28% vs 18%, p <0.001). The 7-year disease specific survival rates for those at highest risk for prostate cancer specific mortality (higher grade pT3a) were 97.6% for cases with negative surgical margins and 92.4% for those with positive surgical margins. Positive surgical margins were associated with a 2.6-fold increased unadjusted risk of prostate cancer specific mortality (HR 2.55, 95% CI 2.02-3.21). Positive surgical margins remained an independent predictor of prostate cancer specific mortality on multivariate analysis (HR 1.70, 95% CI 1.32-2.18). CONCLUSIONS These data demonstrate the independent role of positive surgical margins in prostate cancer specific mortality. These findings support the importance of optimizing surgical techniques to achieve a sound oncological surgical outcome with negative surgical margins when possible.

Accuracy of Digital Rectal Examination and Transrectal Ultrasonography in Localizing Prostate Cancer

Not all prostate cancers are sonographically hypoechoic or palpable on digital rectal examination, and suspicious areas on transrectal prostatic ultrasonography or digital rectal examination often are not cancer. We present quadrant biopsy results from a multicenter prostate cancer screening study in which men were evaluated with prostate specific antigen (PSA) and digital rectal examination. If the PSA level was elevated (greater than 4.0 ng./ml., Hybritech Tandem assay) or digital rectal examination was suspicious quadrant biopsies were performed. Biopsy specimens were labeled separately, and histological findings were correlated by quadrant with the findings on ultrasonography and digital rectal examination. Of the 6,630 subjects enrolled into the study 16% were biopsied. Of 1,002 quadrants that were suspicious on digital rectal examination 110 (11%) had cancer, while 308 of 418 quadrants containing cancer (74%) were not suspicious on digital rectal examination. Of 855 quadrants that were sonographically suspicious 153 (18%) had cancer, while 282 of 435 quadrants containing cancer (65%) were not sonographically suspicious. Of 225 patients with cancer 137 (61%) would have been missed if only the exact site of the palpable induration had been biopsied. Of 251 patients with cancer 131 (52%) would have been missed if only the exact site of the hypoechoic lesion had been biopsied. We conclude that digital rectal examination and transrectal ultrasonography have limited accuracy in identifying and localizing prostate cancer. Our study emphasizes the importance of obtaining systematic biopsies if the PSA level is elevated, even in the absence of digital rectal examination or ultrasound anomalies.

Intense Androgen-Deprivation Therapy With Abiraterone Acetate Plus Leuprolide Acetate in Patients With Localized High-Risk Prostate Cancer: Results of a Randomized Phase II Neoadjuvant Study

PURPOSE Cure rates for localized high-risk prostate cancers (PCa) and some intermediate-risk PCa are frequently suboptimal with local therapy. Outcomes are improved by concomitant androgen-deprivation therapy (ADT) with radiation therapy, but not by concomitant ADT with surgery. Luteinizing hormone-releasing hormone agonist (LHRHa; leuprolide acetate) does not reduce serum androgens as effectively as abiraterone acetate (AA), a prodrug of abiraterone, a CYP17 inhibitor that lowers serum testosterone (< 1 ng/dL) and improves survival in metastatic PCa. The possibility that greater androgen suppression in patients with localized high-risk PCa will result in improved clinical outcomes makes paramount the reassessment of neoadjuvant ADT with more robust androgen suppression. PATIENTS AND METHODS A neoadjuvant randomized phase II trial of LHRHa with AA was conducted in patients with localized high-risk PCa (N = 58). For the first 12 weeks, patients were randomly assigned to LHRHa versus LHRHa plus AA. After a research prostate biopsy, all patients received 12 additional weeks of LHRHa plus AA followed by prostatectomy. RESULTS The levels of intraprostatic androgens from 12-week prostate biopsies, including the primary end point (dihydrotestosterone/testosterone), were significantly lower (dehydroepiandrosterone, Δ(4)-androstene-3,17-dione, dihydrotestosterone, all P < .001; testosterone, P < .05) with LHRHa plus AA compared with LHRHa alone. Prostatectomy pathologic staging demonstrated a low incidence of complete responses and minimal residual disease, with residual T3- or lymph node-positive disease in the majority. CONCLUSION LHRHa plus AA treatment suppresses tissue androgens more effectively than LHRHa alone. Intensive intratumoral androgen suppression with LHRHa plus AA before prostatectomy for localized high-risk PCa may reduce tumor burden.

Pilot study of changes in stretched penile length 3 months after radical retropubic prostatectomy

OBJECTIVES To evaluate changes in stretched penile length after radical retropubic prostatectomy (RRP) in a prospective penile measurement study because an occasional complaint from patients after RRP is that their penis is shortened. METHODS Thirty-one patients undergoing RRP by one surgeon were enrolled. The same physician completed measurements with a paper ruler to the nearest 0.5 cm. The stretched penile length was measured from the tip of the glans to the pubopenile skin junction. The measurements were taken in the preoperative holding area before the patient received anesthetic medication for the RRP and again 3 months postoperatively. The reliability and reproducibility of this measurement were confirmed. RESULTS All 31 patients were measured at 3 months postoperatively. Of the 31 patients, 22 (71%) had a decrease in stretched penile length (range 0.5 to 4.0 cm). Seven were shortened 0.5 cm, 11 were shortened 1.0 to 2.0 cm, and 4 were shortened more than 2.0 cm. Five patients had no change, and in four the penile length was longer (range 0.5 to 1.0 cm). CONCLUSIONS The results of this pilot study appear to show that the stretched penile length decreases after RRP at 3 months of follow-up in most men; 48% (15 of 31) had considerable shortening greater than 1.0 cm. If confirmed by other investigators, the cause of this change needs to be elucidated.

Prostate Specific Antigen Levels in Men Older than 50 Years without Clinical Evidence of Prostatic Carcinoma

In their derivation of normal prostate specific antigen (PSA) levels (0 to 4.0 ng./ml.) Hybritech used almost exclusively men less than 60 years old. The purpose of this study was to define PSA levels by age decade in men older than 50 years without clinical evidence of prostatic carcinoma or so-called cancer-free. We define the cancer-free population as men with a PSA less than or equal to 4.0 ng./ml. and nonsuspicious digital rectal examination, and those with an abnormality in either parameter with a nonmalignant prostate biopsy. A total of 755 men was recruited for a prostate cancer detection study using serum PSA and digital rectal examination, of whom 728 fulfilled our criteria of cancer-free. Newly derived mean and standard deviation were 1.32 +/- 1.10 ng./ml. in the 50 to 59-year group, 1.91 +/- 1.72 ng./ml. in the 60 to 69-year group and 2.36 +/- 1.98 ng./ml. in the 70 to 79-year group. The upper limits for PSA (mean+2 standard deviations) by age were 3.5 ng./ml. in the 50 to 59-year group, 5.4 ng./ml. in the 60 to 69-year group and 6.3 ng./ml. in the 70 to 79-year group. The apparent accuracy of these new limits is strong in the 60 to 69-year group but it declines in the next decade. The data support further attempts at using PSA, age and digital rectal examination to establish selection criteria for prostate biopsy with adequate sensitivity and specificity.