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Identifying appropriate patients as targets for prostate cancer chemoprevention is a daunting task due to the multiple known and unknown factors contributing to patients' risk profiles. Confirmation of the extent and location of early prostate cancers, as well as prostatic intraepithelial neoplasia (PIN), also requires improved image guidance of biopsy to contain costs. Prostate-specific antigen (PSA) in conjunction with transrectal ultrasound (TRUS) and digital rectal examination (DRE) have been the front-line tests for early prostate cancer. Although advances in MRI continue to improve its accuracy, limited availability and higher costs preclude its widespread use for chemoprevention trials. Improved biopsy risk assessment has been achieved by categorizing TRUS grayscale and vascular findings for each biopsy region. In addition, concomitant suspicious TRUS findings also improved cancer yield per biopsy, as well as the amount and grade of tumor per core. However, TRUS remains operator dependent despite advancements in grayscale and vascular imaging. Additional risk parameters are needed to better localize small disease foci and improve the overall diagnostic performance while containing costs. Future work may improve the specificity of tissue characterization to produce reliable noninvasive biomarkers for monitoring chemoprevention responses of early prostate cancer or PIN.

Purpose: The current TNM staging system classifies prostate tumors with abnormal transrectal ultrasound but normal digital rectal examination as clinical stage T2. However, most urologists consider these tumors as clinical stage T1c due to the perceived inaccuracy of transrectal ultrasound in clinical staging. To determine the role of transrectal ultrasound in the clinical staging of prostate cancer we evaluated the pathological stage and disease-free survival of patients undergoing radical prostatectomy who had tumor detected by needle biopsy because of elevated serum prostate specific antigen with or without transrectal ultrasound abnormalities., Materials and Methods: Between 1991 and 1996, 738 patients underwent radical retropubic prostatectomy as monotherapy for clinically localized prostate cancer. Patients were classified into group 1-normal digital rectal examination and transrectal ultrasound (138), group 2-normal digital rectal examination but abnormal transrectal ultrasound (366) and group 3 -abnormal digital rectal examination (234). We compared pathological parameters and disease-free-survival among the 3 groups., Results: Tumors were organ confined in 61%, 42% and 41% of patients in groups 1, 2 and 3, respectively (p = 0.0001). Overall disease-free survival was 80% with a mean followup of 68 months. Disease recurred in 8%, 22% and 25% of patients in groups 1, 2 and 3, respectively (p = 0.007). Group 1 had better disease-free survival compared to groups 2 and 3 (p = 0.003 and p = 0.002, respectively), and there was no difference in disease-free survival between groups 2 and 3 (p = 0.39)., Conclusions: We provide evidence to support the use of transrectal ultrasound findings in the clinical staging system for prostate cancer. Patients with normal digital rectal examination, elevated serum prostate specific antigen and abnormal transrectal ultrasound should be considered as having clinical stage T2 disease.

With the advent of higher-frequency transducers as well as Doppler technologies, TRUS has become a valuable tool in the detection and management of prostate cancer. When combined with the other risk identifiers, an informed patient, and an experienced operator, it cannot only reduce the number of missed cancers by effective targeting of biopsies, but also reduce the number of unnecessary biopsies.

Objectives: To assess the role of clinical parameters and pathologic stage in predicting a positive vesicourethral anastomosis (VUA) biopsy in patients with a rising prostate-specific antigen (PSA) level after radical prostatectomy., Methods: Forty-five patients were referred for a rising PSA level after radical prostatectomy. Transrectal ultrasound evaluation included visualization of the VUA and VUA quadrant biopsies. The rate of positive biopsies (per core and per patient) was correlated with race, PSA level, and the radical prostatectomy pathologic stage., Results: Overall, 53% of patients had a positive biopsy. In multivariate analysis, the dominant independent and synergistic clinical parameters determining positive biopsy rates were a PSA greater than 1 ng/mL at the time of biopsy and the pathologic stage (P = 0.04 and P = 0.02, respectively). Using a PSA cutoff point of 1.0 ng/mL, those patients with organ-confined disease and a PSA of 1.0 ng/mL or less showed no positive cancer cores (low-risk group). Conversely, 89% of patients with extraprostatic extension and a PSA greater than 1.0 ng/mL had a positive biopsy (P <0.01) (high-risk group). Patients with organ-confined disease and a PSA greater than 1.0 ng/mL or extraprostatic extension and a PSA 1.0 ng/mL or less (intermediate-risk group) had a significantly higher chance of having residual cancer than the low-risk group (P <0.025)., Conclusions: The PSA level at the time of biopsy and the pathologic stage of the radical prostatectomy specimen were the strongest determinants of a positive biopsy. A combination of PSA and pathologic stage is useful for decisions regarding VUA biopsy. Patients with organ-confined disease and a PSA of 1.0 ng/mL or less do not appear to benefit from a VUA biopsy, and patients with extraprostatic extension and a PSA greater than 1.0 ng/mL have such a high probability (89%) of local recurrence at the VUA that biopsy may be unnecessary. It appears that VUA biopsy can be restricted to those patients with an intermediate risk (organ-confined disease with PSA greater than 1 ng/mL or extraprostatic extension with a PSA less than 1 ng/mL).

Abnormalities in genes of the apoptotic pathway might contribute to survival in prostatic cancer (PCa) cells after radiation therapy (RT). We investigated the immunohistochemical expression of the products of the p53, p21WAF1, and bcl-2 genes in pre-RT and post-RT biopsy specimens from 38 patients with locally advanced PCa. All of the 38 patients underwent a uniform protocol of RT with or without neoadjuvant hormonal therapy. Immunohistochemical staining for expression of the products of the p53, p21WAF1, and bcl-2 genes was performed on material from pre-RT and post-RT specimens. Sufficient tissue for analysis was available from 25 of the pre-RT and 38 of the post-RT biopsy specimens. In benign prostatic epithelium, RT resulted in expression of p53 (2 [8%] of 25 pre-RT specimens vs. 15 [71%] of 21 post-RT specimens; P < .001) and increased expression of bcl-2 (1 [5%] of 18 pre-RT vs. 18 [86%] of 21 post-RT; P < .001). There was no change in the expression of p21WAF1 (1 [4.5%] of 22 pre-RT vs. 4 [17%] of 23 post-RT; P = NS). Post-RT specimens were positive for PCa in 24 (63%) of 38 cases. In the PCa tissue, p53 expression was seen in 10 (42%) of 24 pre-RT and 12 (63%) of 19 post-RT samples (P = NS). A significant upregulation of p53 was seen in the subgroup of patients who did not receive neoadjuvant hormonal therapy (9 [82%] of 11 vs. 3 [38%] of 8; P = .05). No significant change in p21WAF1 (5 [21%] of 24 vs. 5 [33%] of 15; P = NS), or bcl-2 (4 [18%] of 22 vs. 3 [21%] of 14; P = NS) expression was detected. There was no significant correlation between immunohistochemical expression of apoptosis-related markers and treatment failure. We concluded that RT induced upregulation of the bcl-2 and p53 gene products in benign prostatic tissue and that this likely reflected a protective mechanism in genetically unaltered epithelium. Increased p53 expression in PCa was only seen in patients without neoadjuvant hormonal treatment, indicating that the cancer cells with abnormal p53 were at least partially protected from RT-induced cell death.

Background: The American Cancer Society National Prostate Cancer Detection Project (ACS-NPCDP) was established in 1987. The experience of the ACS-NPCDP demonstrates the yield and impact of periodic examinations for the early detection of prostate cancer., Methods: A cohort of 2999 well men ages 55-70 years was tested annually at 10 clinical centers by prostate specific antigen (PSA), transrectal ultrasound (TRUS), and digital rectal examination (DRE). Biopsies were performed on men with suspicious findings. Pathologic findings were reviewed. The initial study outcomes were the detection yield of multimodality testing and the comparative sensitivity and specificity of the different tests employed. Longer term outcomes included patient quality of life and survival., Results: The cancer detection rate declined significantly across the years of intervention. DRE had lower sensitivity than TRUS or PSA, particularly in later years of follow-up. The specificity of TRUS was lower than that of DRE. Fewer than 9% of the cancers detected in this study were clinically advanced at the time of diagnosis. Ninety-four percent of patients in whom cancer was detected are alive after an average follow-up of 54 months. In one case, death occurred after surgery. Two deaths were attributed to prostate cancer, and eleven other deaths were unrelated to prostate cancer or its treatment., Conclusions: Results of the ACS-NPCDP indicate that a combined-modality approach to prostate cancer detection yields high levels of early detection with infrequent adverse outcomes. Continued follow-up is required to evaluate long term morbidity and mortality.

Background: Estimates of cost-effectiveness for prostate carcinoma screening require a review of current data, modeling efforts, and perspectives on societal impact and costs., Methods: Recent data from the cancer registry of the Michigan Department of Community Health was assessed for incidence trends in relation to age groups and racial differences. Differences in tumor biology between African-American men (AAM) and white men were assessed from a large clinical biopsy series. A review of the literature addressing Markoff modeling to obtain estimates of treatment, screening efficacy, and costs were evaluated., Results: The decline in the incidence of prostate carcinoma since 1992 primarily affected men age > 70 years whereas younger men (age 45-70 years) maintained a 100% greater incidence of localized disease than in 1989, when prostate specific antigen screening became more common. The rate of distant disease has decreased by 60% for both age groups. In the current biopsy series, AAM have distinctly more cores involved with carcinoma and have a higher number of carcinoma cores involved with a Gleason score > or = 7 in men age < or = 70 years with a PSA level < or = 10 ng/ mL (P < 0.05). Markoff models reviewed in the literature demonstrated significant sensitivity to progression, complication, and comorbidity rates. Recent models suggested significant increases in quality-adjusted life expectancy for men choosing radical prostatectomy over watchful waiting if they were age < 70 years and had no severe comorbidities. Original cost estimates from benefit-cost analysis showed similar results of cost per carcinoma and cost per quality-adjusted life-year extension as later cost-effectiveness models., Conclusions: Current diagnostic trends toward the persistent increased detection of localized prostate carcinoma in younger men, combined with a marked reduction in distant stage disease, suggest significant potential mortality reductions. These trends may have greater implications for AAM, but further research is needed to produce models of mortality reduction from emerging data.

Purpose: Will early detection impact on stage of disease and recurrence of prostate cancer in a high risk population? We initiated a community based study to educate and recruit African American men for early diagnosis of prostate cancer, that is the Detroit Education and Early Detection (DEED) study. Our objective was to evaluate our recruitment process for this target population, examine the percentage of organ confined prostate cancer in men undergoing radical prostatectomy and measure recurrence biochemically., Materials and Methods: A community based study from February 1993 to February 1995 through the African American churches in metropolitan Detroit was initiated. We compared the early detection group treated with radical prostatectomy to the population presenting to our urological clinic during the same period. We tested and followed 1,105 African American men using the prostate specific antigen blood test., Results: Pathologically organ confined prostate cancer was diagnosed in 11 of 17 men (65%) who underwent radical prostatectomy in the DEED project. Within the clinic population 35% of the African American men were diagnosed with pathologically organ confined prostate cancer. The difference between the 2 populations was statistically significant (p = 0.033). Disease recurred in 1 of 15 (7%) and 39 of 157 (25%) men in the DEED and clinic populations, respectively (p = 0.97)., Conclusions: We demonstrated our ability to recruit African American men into a prostate cancer early detection program. We diagnosed early but clinically significant prostate cancers among African American men with characteristics similar to prostate cancers diagnosed in other early detection studies in which the overwhelming majority of men were white.

Purpose: To determine the incidence of chronic toxicity and the probability of biochemical and histologic complete response among patients with nonmetastatic prostate cancer, treated with three dimensional (3D) conformal mixed neutron and photon irradiation., Methods and Materials: Between November 1991 and December 1994, 151 patients with prostate cancer were entered in three prospective dose-finding studies of conformal mixed neutron and photon irradiation. Patients with low stage, low to intermediate grade prostate cancer (T1-2NXM0, Gleason Score < or = 7) received 38 Photon Gy (PhGy) plus 9 (51 patients) or 10 (53 patients) Neutron Gy (NGy) to the prostate and seminal vesicles. Forty-seven patients with locally advanced prostate cancer (T3-4 N0-1 M0 and/or Gleason Score > or = 8) received 15 NGy + 18 PhGy to the prostate and seminal vesicles and 9 NGy + 18 PhGy to the pelvic lymph nodes., Results: The median follow-up was 16 months (range: 3-30 months). There was no Grade 3-5 GI or GU toxicity recorded. At 20 months, the actuarial rates of Grade 2 GI morbidity were 6 and 29% for the 9-10 and 15 NGy protocols, respectively (p = 0.07). At 20 months, the incidences of Grade 2 GU morbidity were 4 and 16%, respectively (p = 0.08). Stiffness in flexing or abducting the hips was seen in 20 and 42% of patients receiving 9-10 and 15 NGy, respectively (p = 0.01). Potency was maintained in 65% of all patients. Among patients with an initial PSA < or = 10, 100% had a 12-month PSA < 2 and 78% < 1 ng/ml. Negative postradiation biopsies were seen in 30% of patients 6 months, 79% at 12 months, and 84% of patients at 18 months., Conclusion: The use of conformal mixed neutron and photon irradiation has been well tolerated with no severe bladder or rectal complications observed. However, because of the enhanced toxicity seen with 15 NGy, the current maximum dose levels of neutron irradiation have been limited to 11 NGy.

Background: The American Cancer Society-National Prostate Cancer Detection Project (ACS-NPCDP) is a multidisciplinary evaluation of early prostate cancer detection interventions. This report summarizes the experience of the investigators to date and describes the overall and relative performance of the different detection modalities studied in this project., Methods: Two thousand nine hundred ninety-nine men aged 55 to 70 years at entry who were not already under evaluation for prostate cancer were recruited to participate in up to 5 annual examinations by prostate specific antigen (PSA), digital rectal examination (DRE), and transrectal ultrasound (TRUS). In the course of 5 years of intervention, ACS-NPCDP investigators have completed 9937 examinations, recommended 1215 biopsies, and detected 203 cancers., Results: Loss to cohort follow-up was greatest in the first year. Overall, TRUS led to twice the number of recommendations for biopsy compared with DRE (8.9% versus 4.4%). Elevated PSA was observed in 13.0% of 9535 measurements performed. The overall cancer detection rate declined significantly during the five years of intervention. Detection was significantly associated with age and symptom status at entry. DRE had lower sensitivity compared with TRUS or PSA, particularly in later years of follow-up. The specificity of TRUS was lower than that for DRE. PSA was elevated in 69.2% of examinations that led to cancer detection, compared with only 10.9% when cancer was not found. PSA level, PSA density, and PSA change were all related to the presence of cancer. Less than 6% of the cancers detected in this study were clinically advanced at the time of diagnosis., Conclusions: These data quantify the yield of early cancer detection that may be expected when PSA, DRE, and TRUS are used in populations comparable to the men participating in the ACS-NPCDP. Continued follow-up and further research is needed to assess whether men receiving early prostate cancer interventions benefit as a result.

Background: In hopes of limiting low-yield prostate biopsies, results of digital rectal examination (DRE), transrectal ultrasound (TRUS), prostate specific antigen (PSA) and age-related PSA values, gland-volume-adjusted PSA levels, and longitudinal PSA changes were analyzed to identify their cost-effectiveness as prognostic indicators in screening, biopsy, and follow-up of patients with prostate cancer., Methods: Twenty-nine hundred men with complete data sets from an initial cohort of 2999 men with an annual follow-up for up to 5 years were examined. Intrapatient PSA and gland-volume variability, optimal PSA operating points (o.p.), and test performance scores were determined for each parameter. Decision analysis was then applied retrospectively to each parameter to determine the cancer detection yield, biopsy requirements, and costs for commonly used detection strategies., Results: For the initial screening decision, the optimal PSA o.p. was 3.0 ng/ml but increased to 5.0 ng/ml in combination with DRE, whereas age-related PSA performed no better than did PSA. The mean intrapatient variability in TRUS gland volume (+5.5 cc) relative to mean volume (34 cc) was 16%, which was less than the 28% (0.64/2.3 ng/ml) relative variability for PSA. For biopsy decisions, using PSA density (PSAD) with a level of 0.12 ng/ml/cc there was no significant difference in accuracy compared with the systematic biopsy of all patients with elevated PSA or age-related PSA levels. Rather than perform systematic biopsy on all patients with PSA levels greater than 4 ng/ml, decision analysis showed that a 16-55% reduction in biopsies could be achieved with a respective cancer loss of 4-25% by limiting biopsy to patients with an increased PSAD level and/or abnormal results of DRE. Using age-related PSA criteria in combination with DRE reduced biopsies by 12% but resulted in minimal cost reductions. The greatest biopsy reduction relative to cancer yield and lowest cost per cancer detected occurred with PSAD-driven biopsy strategies. During follow-up, longitudinal changes in absolute PSA and PSAD levels were significantly better (P < 0.05) than the percentage change in PSA levels per year., Conclusions: Cost-effective prostate cancer detection with PSA as a parameter is better achieved if screening and biopsy decisions are not linked intimately. A tailored-biopsy approach for patients with disproportionately elevated PSA levels of suspicious DRE results in the greatest biopsy reduction by selecting lower risk groups for more conservative follow-up.

The American Cancer Society-National Prostate Cancer Detection Project is a prospective, comparative study of a cohort of 2,999 men 55 to 70 years old not suspected on entry of having prostate cancer. A total of 164 prostate cancers is available from this project for analysis. A small proportion of tumors detected were advanced in terms of the clinical stage at diagnosis. Cancer detected by digital rectal examination tended to be more advanced than that found on the basis of only transrectal ultrasound or prostate specific antigen (PSA). A large proportion of patients received curative therapy involving radical prostatectomy in 67.1% and radiotherapy in 18.3%. Of 103 men presumed to have organ confined disease and treated by prostatectomy 64 (37.9%) actually had locally extensive cancer pathologically. PSA level and PSA density were associated with the detection of organ confined cancer but several advanced tumors had PSA levels in the normal range. Age referenced PSA, compared to conventional standards, demonstrated lower sensitivity to cancer with little improvement in specificity. The disease resulting from this multimodality detection effort represented a spectrum of pathological conditions. Further followup and evaluation are needed to determine whether these benefits are reflected in long-term mortality and survival experience.

Our recent cost analysis of prostate cancer early detection evaluated the economic performance of various prostate specific antigen (PSA) screening approaches, detected marginal cost variations with time and used a benefit-cost calculation as a framework for further discussion. Receiver operator characteristic analysis initially suggested an optimal test performance for PSA of 2 to 3 ng./ml. when used alone and at approximately 3 ng./ml. in combination with digital rectal examination. However, lower PSA decision levels require cost justifications. Marginal cost analysis demonstrated markedly decreased use of digital rectal examination by year 3 due to significantly lower sensitivity for incident cancer. The benefit-cost equation acknowledges that many parameters of cost and probability are not definitive to date yet illustrated major points for discussion. The cost parameters most sensitive to incremental change in decreasing order are the specificity of the screening test, benefits obtained from early therapy and prevalence of the disease. Discussions about improving the likelihood of overall benefit for the United States population should focus on these parameters, as well as social and ethical implications. If we assume minimized future expenditures for terminal cancer care via decreases in therapy choices or coverage, no economic benefit for screening exists. If we also assume that potential costs to society are not roughly approximated by any benefits, we may engender inappropriate attempts at cost reduction by effectively discouraging screening in the highest risk groups. Perhaps the greatest immediate cost control issue is the marked increase in prostate cancer detection in the oldest age groups who have the least likelihood of mortality or morbidity benefits. Current cost savings may be possible with improved public health education about the appropriateness of early detection in the oldest age groups or those with significant preexisting medical conditions.

As a significant public health problem, prostate cancer meets nearly all the criteria for screening. While concerns about incomplete natural history, progression rates and need for better prognostic factors are valid, important social and public health issues also need consideration. If future expenditures for terminal cancer care are minimized via reductions in therapy choices or coverage, no economic benefit for prostate cancer screening should exist. Narrowly focused attempts at cost reduction could inappropriately discourage highest risk groups from participating in early detection programs, thereby eliminating the greatest potential benefit of screening. The ACS-NPCDP has demonstrated that early detection of prostate cancer produced distinct stage migration to earlier, more curable disease through optimized use of DRE, TRUS and PSA. PSA is the most objective test and detects tumors of significant biologic potential. Current cost savings are possible with improved public health education about the appropriateness of early detection in the oldest age groups or those with significant pre-existing medical conditions. Prostate cancer control perhaps requires a tailored approach of screening in high risk groups and more appropriate "case finding" in the lower risk general population. The initial combination of PSA and DRE represents an ethical and economical choice for individual patients consulting with informed physicians.

Early detection of prostate cancer has produced distinct stage migration of prostate cancer to earlier, more curable disease through optimized combined use of digital rectal exam (DRE), transrectal ultrasound, and prostate specific antigen (PSA). Currently available and emerging data can be assessed according to the World Health Organization's established criteria. As a significant public health problem, prostate cancer meets almost all the criteria for screening. While concerns about incomplete natural history, progression rates, and the need for better prognostic factors are valid, important social and public health issues also need to be considered. If future expenditures for terminal cancer care are minimized via reductions in therapy choices or coverage, no economic benefit for prostate cancer screening should exist. Narrow-focused attempts at cost reduction could inappropriately discourage high risk groups from participating in early detection programs, thereby eliminating the greatest potential benefit. Conversely, the greatest immediate cost-control issue for prostate cancer care in the United States could be the marked increased detection in men older than 75 years of age. Current cost savings are possible with improved public health education about the appropriateness of early detection in the oldest age groups or those with significant preexisting medical conditions. Prostate cancer control perhaps requires a tailored approach of screening in high risk groups and more appropriate "case finding" in the lower risk, general population. The initial combination of PSA and DRE can result in early detection, which is both ethical and economic, for individual patients consulting with informed physicians.

Background: Different indexes that may enhance the early detection capability of prostate specific antigen (PSA) have been proposed. In addition to the indexes relating to the normal PSA level, there are data suggesting the usefulness of the PSA level relative to prostate gland volume (PSA density), age-referenced PSA level, and PSA change. Little research comparing the sensitivity and specificity of these measures in the same population has been reported., Methods: All subjects were participants in the American Cancer Society National Prostate Cancer Detection Project. Specificity was studied in 2011 men without prostate cancer, and sensitivity was determined for 171 men with prostate cancer., Results: Prostate specific antigen change showed the highest specificity (96.4%), and PSA density the lowest (85.3%). The most sensitive index was PSA density, which was positive for 74.7% of the 171 cases of known cancer. A PSA change of more than 0.75 ng/ml per year was the least sensitive index (54.8%). Sensitivity and specificity varied in a narrow range. Improved performance in specificity was achieved only with the loss of sensitivity., Conclusions: None of the alternative indexes commonly used in general early detection practice demonstrated particular advantage when compared with the normal PSA concentration, defined as no more than 4.0 ng/ml.

Optimal combinations of digital rectal examination (DRE), transrectal ultrasound (TRUS) and prostate specific antigen (PSA) may better detect patients at high risks, as well as those in whom continued screening may not be cost effective. Our recent cost analysis of prostate cancer early detection used current data from three consecutive years of the American Cancer Society's National Prostate Cancer Detection Project. Marginal cost analysis showed marked increased costs for the DRE by year three due to significantly reduced sensitivity for incident cancers. The benefit-cost equation acknowledges that many parameters of both cost and probability are not definitive at this time, yet illustrated major points for discussion. The cost parameters most sensitive to incremental change in decreasing order are: the specificity of the screening test > benefits obtained from early therapy > prevalence of the disease. Benefit-cost calculations demonstrated that DRE, when performed by highly skilled examiners, had the lowest cost. However, DRE became one of the most costly detection scenarios when a minor decrease in DRE performance was assumed for more general examiners. If slightly more specific PSA usage (or assay) is developed, the higher prevalence of clinically detectable prostate cancer could make screening less costly than breast cancer screening. If we assume minimized future expenditures for terminal cancer care via reductions in therapy choices or coverage, no economic benefit for screening exists. If we also assume that potential costs to society are not roughly approximated by any benefits, we may engender inappropriate attempts at cost reduction by effectively discouraging screening in the highest risk groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Few data are available to describe the clinical and pathologic characteristics of prostate cancers detected through early detection programs. The American Cancer Society National Prostate Cancer Detection Project (ACS-NPCDP) is a multimodality, multicenter study of the feasibility of early prostate cancer detection using digital rectal examination (DRE), transrectal ultrasound (TRUS), and prostate specific antigen (PSA). One hundred fifty-six prostate cancers are available from this project for analysis., Methods: The ACS-NPCDP is a prospective, comparative study of a cohort of 2,999 men between 55 and 70 years of age not suspected of having prostate cancer. DRE, TRUS, and PSA are performed for each subject on an annual basis for as long as 5 years. Biopsies are performed on the basis of recommendations from DRE or TRUS results. Although elevated PSA alone was not typically a basis for biopsy, in some instances biopsies were recommended because of the degree of elevation in PSA. Diagnoses are confirmed by participating pathologists and by pathologic analysis., Results: A small proportion of cancers detected were advanced in terms of the clinical stage at time of diagnosis. A total of only six cancers were stage C1 to D1, and five of these were preexisting cancers detected at the first examination. Cancers detected by DRE tended to be more advanced than those found on the basis of only TRUS or PSA. A large proportion of patients received curative therapy, involving radical prostatectomy for 67.9% and radiation therapy for 17.9%. Of 100 men presumed to have organ confined disease and treated by prostatectomy, 64 actually proved to have localized cancer, a rate of upstaging of 36.0%. PSA level and PSA density were associated with the detection of organ confined cancer, but several advanced cancers had PSA levels in the normal range, limiting the usefulness of these measures for staging., Conclusions: The cancers resulting from this multimodality detection effort represented a spectrum of pathologic findings. These data, however, suggest that early detection interventions in men not suspected to have prostate cancer will yield tumors with a favorable stage distribution that are likely to benefit from treatment. Further follow-up evaluation is needed to determine whether these benefits are reflected in long-term mortality and survival experience.

Cost-effectiveness calculations of prostate cancer early detection have not been possible due to the lack of any data demonstrating reduction in mortality from any test or procedure. Prior analyses focused only on cost assessments without consideration of any possible benefits. We used current data from three consecutive years of the American Cancer Society-National Prostate Cancer Detection Project to assess different economic perspectives of test performance, marginal costs, and benefit-cost analysis. The marginal cost, or cost per cancer, of digital rectal examination (DRE) markedly increased by the third year relative to several proposed prostate-specific antigen (PSA) scenarios. Sensitivity analysis for average cost showed that at 4 ng/ml, pricing PSA below $30 would be the most potent factor in potentially lowering costs. Analysis of receiver operator characteristic curves suggested that optimal performance for PSA may be at 3 ng/ml when combined with DRE or between 2 to 3 ng/ml when used alone. Benefit-cost calculations demonstrated that DRE when performed by highly skilled examiners had the lowest cost. However, DRE became one of the most costly detection scenarios when a minor decrease in performance was assumed. Sensitivity analysis demonstrated that the three most determinant parameters of net benefit, in decreasing order, are: specificity, benefits from earlier therapy, and prevalence. If a slightly more specific PSA assay is developed, the higher prevalence of clinically detectable prostate cancer could also make screening less costly than breast cancer screening. Under the assumptions of these analyses, the combination of PSA and DRE appears to represent an ethical and economical detection choice for individual patients in consultation with their physicians. Additional research is needed to quantify the significance of differences between different screening strategies.

Current staging of early prostate cancer separates patients into two groups: those with palpable and non-palpable tumors. Such staging relies on digital rectal examination in making this separation, despite the low sensitivity, low specificity, and low positive predictive value of this method. As an alternative, tumor volume may be useful for staging because of its powerful prognostic ability and its potential to be assessed clinically due to recent advances in imaging techniques such as transrectal ultrasound. In this study, we evaluate the utility of tumor volume in predicting progression of early prostate cancer based on the composite published evidence from nine pathologic studies of serially-sectioned prostates. Logistic regression revealed that tumor volume was a good positive predictor of all measures of tumor progression. There was a 10 percent probability of capsular invasion in tumors measuring about 0.5 cm3; 10 percent probability of seminal vesicle invasion in tumors measuring about 4.0 cm3; and 10 percent probability of metastases in tumors measuring about 5.0 cm3. These composite results suggest that tumor volume is a significant predictor of cancer progression. A volume-based prognostic index is proposed as an adjunct to staging for early prostate cancer.

Screening for prostate cancer represents a clinical dilemma with no clear evidence to suggest decreased mortality from any diagnostic test. We now possess new knowledge regarding optimal combinations of DRE, TRUS, and PSA. While DRE and TRUS may be too subjective and PSA too nonspecific, their combined predictive values identify not only men at high risk but also those for whom continued frequent screening may not be cost effective. A monoclonal PSA decision level of no more than 4.0 ng/ml should be used, since 40 percent of cancers detected from 4.0 to 10.0 ng/ml already have extracapsular extension. Assuming that DRE is performed by experienced examiners, the combination of PSA and DRE should produce cost-effective early detection and minimize missed cancers below 4.0 ng/ml. TRUS should be reserved for those patients with either PSA elevations and/or DRE abnormalities. The use of TRUS gland volume data to further modify PSA decision levels, such as the "predicted" PSA concept, may also improve TRUS biopsy criteria and predictive values. Prostate cancer detection can then be objectively limited to a small percentage of the population and better selected for earlier, more localized disease. The ultimate decrease in mortality from screening remains to be demonstrated in randomized trials or observed only after decades of increased public awareness about prompt early detection combined with effective, definitive therapy.

Methods: The diagnostic performance of transrectal ultrasound (TRUS) gland volume and prostate specific antigen (PSA) results were evaluated in 204 men consecutively scheduled to undergo transurethral prostatic resection (TUR)., Results: Nonpalpable prostate cancer was detected by TRUS alone in 18% (29 of 161) and by TUR alone in 9% (14/161), for an overall cancer incidence of 27%. A predicted PSA value (TRUS gland volume x 0.20 ng/ml/g = polyclonal PSA) was used for comparison with serum PSA for each patient. TRUS positive predictive value improved from 52% to 86% when serum PSA exceeded the predicted value. The specificity and positive predictive value of PSA at 2.5 ng/ml were 23% and 37%, respectively, which increased to 88% and 72%, respectively, when serum PSA exceeded the predicted value., Conclusions: Predicted PSA values produce decision levels near the 95th percentile for each patient and assist individual biopsy decisions better than grouped gland volume ranges. Wider application of TRUS and PSA in any clinical setting or early detection program is now possible.

The American Cancer Society National Prostate Cancer Detection Project is a prospective, multidisciplinary, and multicenter trial to assess the potential for early detection of prostate cancer by transrectal ultrasonography (TRUS), digital rectal examination (DRE), and serum prostate-specific antigen assay (PSA). By November 1990, 2805 men between the ages of 55 and 70 years with no known signs or symptoms of prostate cancer were enrolled in the study, which is planned to run for 5 years. Annual TRUS, DRE, and PSA tests were done on these subjects, and biopsies were recommended for suspicious lesions when detected. To study the performance of PSA testing in presumed normal subjects, all men were eliminated who had (1) prostate cancer detected on their initial examinations and proven by biopsy or (2) cancer detected during the year or subsequent examinations. Additionally, all men with TRUS or DRE findings that were interpreted as suspicious for cancer but who are being followed and have not yet had biopsies done were removed from this series. This left a unique, extensively screened group of 1695 men who were free of prostate cancer, as far as could be determined. Analyses of the PSA levels in this large population in the appropriate age range for increasing risk of prostate cancer revealed several important findings. First, there was a direct relationship between serum PSA levels and estimated prostate volume for both the currently available monoclonal and polyclonal PSA assays. Individuals with benign prostatic hyperplasia and larger gland volume have a higher normal limit of PSA than men with normal gland volume. Second, analyses showed no relationship between age and PSA levels or between symptoms of prostatism and PSA levels independent of gland enlargement. It was concluded that volume-adjusted upper limits of normal PSA can be determined for different levels of specificity desired. This information may be applicable to the use of PSA in men not already suspected of having prostate cancer and may increase its effectiveness as a tool for early detection.

In a study population, can digital rectal examination (DRE), transrectal ultrasound (TRUS), and prostate specific antigen (PSA) (monoclonal) effectively detect the majority of clinically relevant cancer? If this is possible, the remaining patients could then be considered for chemopreventive protocols. The American Cancer Society/National Prostate Cancer Detection Project (ACS/NPCDP) had a cancer detection rate of 2.4% for its initial year utilizing PSA, DRE and TRUS. TRUS and PSA detected 73% more cancer than DRE alone. TRUS detected a greater percentage of cancers than DRE (85% vs. 64%). PSA was > or = 4 ng/ml for 66% of prostate cancer patients; 11% of cancer patients had PSA < 2 ng/ml. PSA decision levels based on gland volume detected a subgroup at the 95th percentile that had a nine-fold increased risk for cancer. In a separate study differentiating benign prostatic hypertrophy (BPH) and cancer, we found 0.12 +/- 0.13 ng/ml/gm for serum PSA (sPSA)/gm BPH. This study proved that predicted PSA (pPSA) = gland volume x 0.12; this equation also functioned at the 95th percentile for any individual patient. Individual patient assessment: 1. Entry level PSA = 2 ng/ml. 2. Those patients with PSA > 2 ng/ml have TRUS determination of gland volume (performed by technician). 3. pPSA = gland volume x 0.12. If sPSA > pPSA then: 4. (sPSA-pPSA)/2 = predicted volume (cc) of cancer; 5. 3 square root of volume of cancer = mean diameter (cm) of cancer. Thus, these results should detect the majority of clinically relevant cancer (> 0.5 cc). PSA combined with TRUS and DRE can identify high risk groups for cancer.

To investigate whether radiologists can objectively define a high-risk group for prostate cancer, the researchers measured gland volume and compared it with results of a screening blood test, prostate-specific antigen (PSA) assay. A total of 768 men, aged 55-71 years, were self-referred to two prostate cancer screening programs using transrectal ultrasound (US) and digital rectal examination. In patients with no evidence of cancer, statistically significant increases in mean PSA values were noted with increasing gland volume ranges (P less than .05). PSA values in patients with cancer were more likely to exceed the volume-adjusted 95th percentile (mean + [1.65.standard deviation]) than those in patients with negative biopsy results (P less than .005). Patients with PSA values above the volume-adjusted 95th percentile have an estimated risk for prostate cancer up to nine times that of the general screening population. The researchers conclude that knowledge of transrectal US gland volume and prostate-specific antigen assay type are important objective variables for future prostate cancer screening programs. The volume-adjusted 95th percentiles presented may help guide cost-effective management of current early detection efforts.

A screening study with transrectal ultrasound (US) and digital rectal examination to diagnose early prostate cancer was performed to calculate diagnostic costs. The total costs of screening 784 men were $130,400 with transrectal US and $41,080 with digital rectal examination. Per diagnosed cancer, the costs were $6,520 for transrectal US and $4,108 for digital rectal examination, a difference of 37%. The costs per early diagnosed cancer (stage A or B) were $7,671 and $5,869 for transrectal US and digital rectal examination, respectively--a difference of 23%. The costs per early cancer that would have been advanced if diagnosed without screening were $22,177 for transrectal US and $28,528 for digital rectal examination--a difference of 22% in favor of transrectal US. Equations for these relative costs were generated for transrectal US and digital rectal examination. Costs are related to changes in prevalences and to changes in the stages of prostate cancer when diagnosed without screening.

A study was undertaken to assess the ability of transrectal ultrasound (TR/US), digital rectal examination (DRE), and Prostate Specific Antigen (PSA), to diagnose persistent prostate cancer following an I125 seed implant (SI). Twenty-six patients formed the study group. The median follow-up time was 38 months, and the range was 20 to 60 months. Eighty-eight percent (23/26) had suspicious lesions on TR/US, followed by ultrasound-guided biopsies. Biopsies were performed only on those patients having suspicious lesions on TR/US. Histologically proven adenocarcinoma was found in 81% (21/26) of the patients. Statistical evaluation was done using tissue obtained at biopsy as the "gold standard." The sensitivities for the DRE and PSA were 33% and 76%, respectively. The specificities for DRE and PSA were 50% and 0%, respectively. The positive predictive values for cancer were 91% by TR/US, 100% by DRE, and 89% by PSA. The negative predictive values were 13% for DRE and 0% for PSA. Overall detection rates (N = 26) were 81% for TR/US, 27% for DRE, and 62% for PSA. We conclude that ultrasound criteria for the presence of cancer are the same for both the post-irradiated prostate and the untreated prostate, and that TR/US is the most sensitive test for the diagnosis of persistent local cancer following I125 seed implantation.

The authors examined 784 self-referred men over age 60 years to compare clinical usefulness of transrectal ultrasound (US) and digital rectal examination in a screening program for prostate cancer. Biopsy was performed in 77 cases, 83% (64 of 77) for abnormalities detected with transrectal US and 38% (29 of 77) because of findings at digital examination. Twenty-two cancers were detected, 20 with transrectal US and ten at digital examination. Overall detection rate for prostate cancer with transrectal US was two times higher than that with digital examination (2.6% vs 1.3%). Sensitivity, specificity, and negative predictive value for transrectal US and digital examination were calculated for a range of prevalences (0.028-0.1543). Sensitivity was two times higher for transrectal US than for digital examination. Transrectal US demonstrated 100% (17 of 17) of tumors with the most favorable prognosis (less than or equal to 1.5 cm in diameter) compared with 41% (seven of 17) for digital examination. The authors conclude that transrectal US is more sensitive than digital examination in the detection of prostate cancer, and they advocate broader implementation and evaluation of transrectal US as a tool for early detection.

Biplanar, transrectal ultrasound (US) guidance of needles was used in the transperineal biopsy of possibly malignant prostatic lesions in 80 patients (83 biopsies). A 22-gauge cytologic needle was used to locate and fixate the lesion, and aspiration specimens for cytologic and histologic evaluation were obtained (with 22- and 14-gauge needles, respectively). Twenty-one 19-gauge needle core biopsies were also performed. Forty-nine patients (61%) had histologically prove adenocarcinoma. The rate of cancer diagnosis was 53% with cytologic evaluation and 54% with histologic evaluation (combined yield, 61%). This included 34% of cancers less than 1.0 cm in diameter and 56% of those 1.0-1.5 cm. Thirteen of 23 (57%) of these lesions were nonpalpable or equivocal on digital rectal examination. These results suggest that transrectal US guidance of thin-needle biopsies is useful in diagnosing early prostate cancer.

In the authors' experience, transrectal sonography has the ability not only to stage prostatic cancer accurately, but also to detect such lesions before they become palpable.

Two hundred fifty-six patients with hypoechoic lesions of the prostate found at transrectal ultrasound (US) were evaluated with prostate-specific antigen (PSA) study, digital rectal examination (DRE), and US-guided transrectal biopsy. Positive predictive values for cancer were calculated for transrectal US alone and in combination with DRE, PSA study, or both. Results were correlated with lesion size. The positive predictive value for transrectal US alone was 41%; this value increased to 61% if the patient had positive results from DRE, 52% if the PSA level was elevated, and 71% if both the DRE results and PSA level were abnormal. The positive predictive value for transrectal US fell to 24% if results of the DRE were normal, 12% if the PSA level was normal, and 5% if both DRE results and PSA level were normal. No cancers were detected in lesions 1.0 cm or smaller if DRE results and PSA level were normal. DRE and PSA study are valuable complements to abnormal transrectal US examinations. Biopsy of small suspicious lesions may not be indicated if results of both of the studies are normal.

Indications for TRUS are: (a) for diagnosis of nonpalpable cancer, or detection of cancer with greater accuracy than is possible at present; (b) for guidance of transrectal biopsies of hypoechoic lesions for histologic confirmation of cancer; (c) for guidance of staging biopsies to ensure diagnoses of extraprostatic extension; and (d) for staging previously diagnosed prostate cancer.