Michael K. Brawer

Radical Prostatectomy versus Observation for Localized Prostate Cancer

BACKGROUND The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known. METHODS From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality. RESULTS During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P=0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P=0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P=0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P=0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death. CONCLUSIONS Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. (Funded by the Department of Veterans Affairs Cooperative Studies Program and others; PIVOT ClinicalTrials.gov number, NCT00007644.).

The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia

BACKGROUND Men with benign prostatic hyperplasia can be treated with alpha 1-adrenergic-antagonist drugs that relax prostatic smooth muscle or with drugs that inhibit 5 alpha-reductase and therefore reduce tissue androgen concentrations. However, the effects of the two types of drugs have not been compared. METHODS We compared the safety and efficacy of placebo, terazosin (10 mg daily), finasteride (5 mg daily), and the combination of both drugs in 1229 men with benign prostatic hyperplasia. American Urological Association symptom scores and peak urinary-flow rates were determined at base line and periodically for one year. RESULTS The mean changes from base line in the symptom scores in the placebo, finasteride, terazosin, and combination-therapy groups at one year were decreases of 2.6, 3.2, 6.1, and 6.2 points, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). The mean changes at one year in the peak urinary-flow rates were increases of 1.4, 1.6, 2.7, and 3.2 ml per second, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). Finasteride had no more effect on either measure than placebo. In the placebo group, 1.6 percent of the men discontinued the study because of adverse effects, as did 4.8 to 7.8 percent of the men in the other three groups. CONCLUSIONS In men with benign prostatic hyperplasia, terazosin was effective therapy, whereas finasteride was not, and the combination of terazosin and finasteride was no more effective than terazosin alone.

Screening for prostatic carcinoma with prostate specific antigen.

Prostate specific antigen (PSA), neutral serine protease secreted exclusively by prostatic epithelial cells, has a number of applications in the management of men with prostatic carcinoma. While it is widely recognized that elevated PSA correlates with the presence of carcinoma, little data exist regarding the use of PSA as the initial test in the early detection of prostatic cancer. We measured serum PSA levels in men older than 50 years and performed digital rectal examination and ultrasound guided prostate biopsy of those who had a PSA level of greater than 4.0 ng./ml. A total of 1,249 men entered the protocol, of whom 187 (15.0%) had PSA levels above 4.0 ng./ml. Digital rectal examination and ultrasound guided biopsy were performed at our facility in 105 patients (56.2%). A total of 32 carcinomas (30.5%) was detected, including 23 in men with PSA between 4.1 and 10.0 ng./ml. and 9 in men with a PSA of greater than 10.0 ng./ml. Of the 32 carcinomas 12 (37.5%) occurred in men with normal prostates or glands demonstrating only asymmetry on digital rectal examination, and 3 men had carcinoma despite normal digital rectal examination and no hypoechoic peripheral zone lesion detected on ultrasound. Of the 32 patients 30 had clinically localized carcinoma but 7 of the 16 undergoing radical prostatectomy had pathological upstaging. We conclude that PSA represents an important adjunct to digital rectal examination for the early detection of prostatic carcinoma. The efficacy of this or any other early detection test to decrease prostate cancer mortality necessitates the results of prospectively randomized clinical trials.

Prostatic Intra-Epithelial Neoplasia and Early Invasion in Prostate Cancer

Prostatic intra‐epithelial neoplasia (PIN, or intraductal dysplasia) is considered a precursor of invasive carcinoma, characterized by proliferation and anaplasia of cells lining prostatic ducts and acini. The highest grade of PIN, Grade 3, is thought to represent carcinoma in situ. To quantitate the degree of disruption of the basal cell layer in human prostatic ducts and acini as a potential marker of early invasion in PIN, a monoclonal antibody to keratin proteins of 49, 51, 57, and 66 kd which selectively labels the prostatic basal cell layer was used. A total of 1093 acini with PIN were identified in 14 cases with invasive carcinoma. Tumor cells consistently failed to be decorated with this antibody. The frequency of disruption of the basal cell layer increased with increasing grades of PIN, with disruption present in 0.7% of cases of PIN 1, 15% of cases of PIN 2, and 56% of cases of PIN 3. The amount of disruption of the basal cell layer also increased with increasing grades of PIN, with loss of more than one third of the basal layer in 52% of foci of PIN 3 compared with less than 2% in lower grades of PIN. Disruption of the basal layer was more common in acini adjacent to invasive carcinoma than in distant acini. These findings suggest that early invasion in prostate cancer is characterized by disruption of the basal layer, and that invasion occurs commonly in association with foci of high‐grade prostatic intra‐epithelial neoplasia. Cancer 59:788‐794, 1987.

Predictors of pathologic stage in prostatic carcinoma. The role of neovascularity

Background. Prostate adenocarcinoma is a significant cause of morbidity and mortality in older men. However, the histologic prevalence far exceeds clinically manifest disease. Increased screening has resulted in the detection of a large number of carcinomas of unknown malignant potential. The authors investigated tumor angiogenesis to predict pathologic stage in prostatic tumors. Angiogenesis in prostatic intraepithelial neoplasia (PIN), a putative premalignant lesion, also was investigated.

Comparison of microscopic vascularity in benign and malignant prostate tissue

A variety of malignant neoplasms have been shown to induce capillary neovascularization, and in some cases the degree of vascularization appears to correlate with aggressive behavior and risk of metastasis. We hypothesized that carcinoma of the prostate also induces the formation of new capillaries, and we developed a method to quantify the relative density of microscopic vessels in carcinoma of the prostate compared with benign prostatic glandular tissue. The number of microvessel profiles in tissue sections was quantified by marking the vascular endothelial cells with antibodies to factor VIII-related antigen using standard immunohistochemistry techniques and comparing fields of adenocarcinoma with benign glandular tissue in 15 radical prostatectomy specimens. The analysis was facilitated by using the Optimas computerized image analysis system (Bioscan, Seattle, WA) with software written for this investigation. Fourteen of the 15 cases demonstrated significantly higher vascular density in the areas of carcinoma than in the benign tissues. Overall, the ratio of vessels per unit area in sections of carcinoma versus benign tissue was approximately double (ratio = 2.02; P < .001). In benign tissues the capillaries are restricted for the most part to the periglandular stroma immediately adjacent to the epithelium, whereas the distribution in carcinoma appears to be more random. The data demonstrate the increased density of capillaries in prostatic carcinoma when compared with benign prostate tissue.

Comparison of percent free PSA, PSA density, and age-specific PSA cutoffs for prostate cancer detection and staging.

OBJECTIVES Various methods have been proposed to increase the specificity of prostate-specific antigen (PSA), including age-specific PSA reference ranges, PSA density (PSAD), and percent free PSA (%fPSA). In this multicenter study, we compared these methods for their utility in cancer detection and their ability to predict pathologic stage after radical prostatectomy in patients with clinically localized, Stage T1c cancer. METHODS Seven hundred seventy-three men (379 with prostate cancer, 394 with benign prostatic disease), 50 to 75 years old, from seven medical centers were enrolled in this prospective blinded study. All subjects had a palpably benign prostate, PSA 4.0 to 10.0 ng/mL, and a histologically confirmed diagnosis. Hybritechs Tandem PSA and free PSA assays were used. RESULTS %fPSA and age-specific PSA cutoffs enhanced PSA specificity for cancer detection, but %fPSA maintained significantly higher sensitivities. Age-specific PSA cutoffs missed 20% to 60% of cancers in men older than 60 years of age. %fPSA and PSAD performed equally well for detection (95% sensitivity) if cutoffs of 25% fPSA or 0.078 PSAD were used. The commonly used PSAD cutoff of 0.15 detected only 59% of cancers. %fPSA and PSAD also produced similar results for prediction of the post-radical prostatectomy pathologic stage. Patients with cancer with higher %fPSA values (greater than 15%) or lower PSAD values (0.15 or less) tended to have less aggressive disease. CONCLUSIONS The results of this study demonstrated that cancer detection (sensitivity) is significantly higher with %fPSA than with age-specific PSA reference ranges. %fPSA and PSAD provide comparable results, suggesting that %fPSA may be used in place of PSAD for biopsy decisions and in algorithms for prediction of less aggressive tumors since the determination of %fPSA does not require ultrasound.

The Inability of Prostate Specific Antigen Index to Enhance the Predictive Value of Prostate Specific Antigen in the Diagnosis of Prostatic Carcinoma

The prostate specific antigen (PSA) level has become an important but imperfect means of detecting prostatic carcinoma. PSA index (serum PSA normalized to estimated gland volume) has been suggested to improve the performance characteristics of PSA alone. In an attempt to confirm this observation, we compared serum PSA alone to the PSA index in 218 men undergoing systematic random prostatic needle biopsy. Total gland PSA index as well as nontransition zone PSA index were calculated using several constants for the estimated contribution to the serum PSA from the transition zone. The Mann-Whitney nonparametric analysis was performed to account for differences in variances within the data set. For the patient population as a whole, all methods of testing were approximately equivalent in the ability to provide a statistically significant (p < 0.01) stratification between patients with benign and malignant biopsies. In patients with a serum PSA level of 4.1 to 10.0 ng./ml. none of the tests was able to distinguish those with carcinoma from those with a benign biopsy. In men with a normal prostate on digital rectal examination serum PSA was superior to other tests in predicting biopsy results. We conclude that PSA index does not enhance the ability of serum PSA alone to predict the presence of carcinoma.

REPEAT PROSTATE NEEDLE BIOPSY: WHO NEEDS IT?

The indications for repeat prostate needle biopsy after a transrectal ultrasound guided sextant biopsy are not defined. We examined 100 sextant prostate needle biopsies without a diagnosis of malignancy, which were repeated. Carcinoma was detected in 20 repeat biopsies (20%). Stratification based on initial biopsy result revealed carcinoma in 10 of 69 cases (14.5%) without prostatic intraepithelial neoplasia or atypia, 5 of 17 (29.4%) with atypia, 5 of 5 (100%) with grade II or III prostatic intraepithelial neoplasia and 0 of 9 with grade I prostatic intraepithelial neoplasia. Examination of prostate specific antigen (PSA) levels and PSA velocity did not provide statistically significant stratification, perhaps due to the wide variance in these parameters and the small sample size. We conclude that patients with a diagnosis of glandular atypia, or grade II or III prostatic intraepithelial neoplasia on initial biopsy are at high risk for invasive carcinoma and should undergo repeat prostate needle biopsy. A rapidly increasing serum PSA level or grossly abnormal digital rectal examination may also indicate carcinoma not discovered on initial biopsy.

Expression of metalloproteinase genes in human prostate cancer

SummaryTwenty-five surgical specimens of malignant human prostate, 3 lymph nodes with metastatic prostate carcinoma, 11 normal human prostates, as well as 3 human prostate cell lines (DU-145, PC3 and LNCaP) were examined for the expression of the human matrix metalloproteinase-7 gene (MMP-7) from the human collagenase family (originally called PUMP-1 for putative metalloproteinase-1) [Quantin et al. (1989) Biochemistry 28:5327–5334; Muller et al. (1988) Biochem J 253:187–192; Matrisian and Bowden (1990) Semin Cancer Biol 1:107–115]. Northern blots were prepared using total RNA extracted from 18 prostate adenocarcinomas, 2 lymph nodes with metastatic prostate carcinoma and 11 normal human prostates. When the northern blots were hybridized with a32P-labeledMMP-7 cDNA probe, a 1.2-kb mRNA was detected in 14 out of 18 prostate adenocarcinomas, 1 out of 2 metastatic lymph nodes, and 3 out of 11 normal prostates. The 3 human prostate cell lines did not show any evidence of theMMP-7 transcript. In situ hybridization was conducted to localize theMMP-7 mRNA to individual cells using a35S-labeledMMP-7 cRNA. In situ hybridization was carried out on snap-frozen tissue sections of 7 prostate adenocarcinomas and 3 lymph nodes containing metastatic prostate adenocarcinoma using the same tissues previously probed by northern analysis as well as new samples. In situ hybridization revealed that theMMP-7 gene was expressed in the epithelial cells of primary prostate adenocarcinoma as well as in invasive and metastatic cells.MMP-7 expression was also seen focally in some dysplastic glands but not in stroma. Additional northern blot analysis was performed using probes to human type-IV collagenase, type-I collagenase and stromelysin I in human prostate adenocarcinoma as well as normal prostate tissue. Our results indicated that 6 out of 10 adenocarcinoma samples and none of the 4 normal samples were positive for type-IV collagenase transcripts. Tissue samples were also examined for the expression of type-I collagenase (9 adenocarcinomas and 4 normal) and stromelysin I (13 adenocarcinomas) by northern analysis. None of the tissues was found to express the transcripts of interest at detectable levels. These data suggest that certain metalloproteinases are present in prostatic adenocarcinoma and may play a role in invasion and metastasis.