Partin tables: past and present.
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Biomedical subjects
Publications and source records attributed to A W Partin.
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BACKGROUND: Considerable evidence has shown that the use of computational algorithms to combine pretreatment clinical and pathology results can enhance predictions of patient outcome. The aim of this study was to prove that the application of such methods to predict patient-specific likelihoods of organ-confined (OC) prostate carcinoma (PCA) may be helpful to patients and physicians when they are choosing an optimal treatment for carcinoma of the prostate. METHODS: The authors used clinical and quantitative pathology results from the biopsy specimens of 817 PCA patients who had been evaluated at a large national pathology reference laboratory. The pathology parameters that were measured included the number of positive cores, Gleason grades and score, percentage of tumor involvement, and the tumor location. The pathologic stage of these cases, as determined by results from radical prostatectomy, lymphadenectomy, or bone scan, categorized the PCA as either OC, non-OC due to capsular penetration only (NOC-CP) or advanced disease with metastasis (NOC-Mets), i.e., seminal vesicle and/or lymph-node positive or bone-scan positive. There were a total of 481 OC cases, 185 NOC-CP cases, and 151 NOC-Mets cases. Patient-specific prediction models were trained by ordinal logistic regression (OLOGIT) and genetically engineered neural networks (GENNs), and the resulting trained models were validated by biopsy information from an independent set of 116 PCA patients. RESULTS: When the authors applied a cutoff of >or= 35% for the n = 817 training set of OC, NOC-CP, and NOC-Mets predictive probabilities, the OLOGIT model predicted OC PCA with an accuracy of 91%, whereas the GENN model predicted the same with an accuracy of 95%. When the authors employed the n = 116 validation set (76 OCs, 31 NOC-CPs, and 9 NOC-Mets), the OLOGIT and GENN models correctly identified OC PCA with 91% and 97% accuracy, respectively. CONCLUSIONS: The value of combining patient pretreatment diagnostic pathology parameters to make predictions concerning the postoperative extent of pathology was illustrated clearly in this study. This finding further confirms the need to pursue such approaches for PCA disease management in the future, especially with the increasing prevalence of clinical T1c (American Joint Committee on Cancer, 1977) disease.
BACKGROUND: Currently, the standard for predicting pathologic stage from information available at the time of prostate biopsy is the "Partin nomograms" that were derived using logistic regression analysis. The authors retrospectively reviewed a large series of men with clinically localized prostate carcinoma who underwent staging pelvic lymphadenectomy and radical retropubic prostatectomy. They then utilized pathologic and clinical data at the time of prostate biopsy to develop and test an artificial neural network (ANN) to predict the final pathologic stage for this group of men. They then compared the results of ANN with the previous nomograms. METHODS: Five thousand seven hundred forty-four men were treated at the authors' institution from 1985 to 1998. An ANN was developed using two randomly selected training and validation sets for predicting pathologic stage. Input variables included age, preoperative serum prostate specific antigen level, clinical TNM (tumor, lymph node, and metastasis) classification, and Gleason score from the biopsy specimen. Outcomes included organ confinement and lymph node involvement status. RESULTS: The ANN was slightly superior to the nomograms in predicting pathologic stage, such as organ confinement and lymph node involvement status. CONCLUSIONS: In predicting organ confinement and lymph node involvement status, ANN was more accurate and had a larger area under ROC than the nomograms based on the logistic regression method. Artificial neural network models can be developed and used to better predict final pathologic stage when preoperative pathologic and clinical features are known.
BACKGROUND: Transrectal prostate biopsy decisions often have been based on absolute cutoff values for total and free prostate-specific antigen (PSA). The authors decided that it would be more appropriate to develop risk profiles for the individual patient to allow him to decide whether to undergo a prostate biopsy. METHODS: To develop risk profiles, the authors first used multivariate logistic regression analysis to analyze 2054 males who were part of the Tyrol (Austria) PSA Screening Project. Second, artificial neural network (ANN) analyses were performed using data from 3474 males who also were part of the Tyrol PSA Screening Project and who had undergone prostate biopsy. These analyses were compared with standard cutoff levels of specificity for the detection of prostate carcinoma. RESULTS: To the authors' knowledge, this was the first time that multivariate logistic regression analysis was used to decide whether to perform prostate biopsies based on risk profiles rather than on single cutoff levels. For the detection of prostate carcinoma, at sensitivity levels of 90--95%, the ANN was 150--200% more specific than the standard cutoff points. For screened volunteers with total PSA levels below 4 ng/mL, ANN showed a lower cancer predictive ability in comparison with volunteers with total PSA levels above 4 ng/mL. However, the ANN was approximately 150--200% more specific than the standard cutoff levels in both groups. CONCLUSIONS: At high sensitivity levels, ANN increased the specificity for prostate carcinoma detection in a PSA-based screened population. The improvement in specificity between standard cutoff levels and ANN ranged between 150--200% and was not affected by the presence of benign prostatic hyperplasia or prostatitis.
Prostate cancer chemoprevention represents a relatively new and promising strategy for reducing the immense public health burden of this devastating cancer of men in the United States and Western societies. Chemoprevention is defined as the administration of agents (drugs, biologics, and natural products) that modulate (inhibit) one or more steps in the multistage carcinogenesis process culminating in invasive adenocarcinoma of the prostate. In 2000, there were an estimated 170,000 new cases of prostate cancer and 31,000 deaths in the United States. During the past decade, the National Cancer Institute (NCI) organized the chemoprevention research program and began testing the first generation of promising agents (eg, 4-(hydroxy)-fenretinide [4-HPR], difluoromethylornithine [DFMO], antiandrogens) in high-risk cohorts and launched the first-large scale US phase 3 primary prevention trial, known as Prostate Cancer Prevention Trial (PCPT-1), in 18,000 average-risk men (age more than 55 years and prostate-specific antigen [PSA] less than 3 ng/mL) treated for 7 years with finasteride or placebo. In the summer of 1998, the NCI Prostate Cancer Progress Review Group (PRG) Report to the director of NCI was published in response to the leadership of the prostate cancer advocacy community in conjunction with Congress. To further elucidate and address critical issues identified in this report and to develop a research agenda for the newly created Prostate and Urologic Cancer Research Group in the Division of Cancer Prevention at NCI, the NCI organized the workshop "New Clinical Trial Strategies for Prostate Cancer Chemoprevention." The major objectives were to promote understanding and cooperation among the NCI, US Food and Drug Administration (FDA), academia, pharmaceutical industry, and the public regarding new opportunities for clinical prevention trials for prostate cancer. The workshop was divided into three concurrent breakout panels and a fourth joint integrative panel. The workshop addressed multiple key areas identified in the PRG report in the following panels: (1) Molecular Targets and Promising Agents in Clinical Development; (2) Intermediate Endpoint Biomarkers for Prevention Trials; (3) High-Risk Study Populations for Prevention Trials, and (4) Preventive Clinical Trial Designs and Regulatory Issues. Expert panelists were drawn from leading academic, pharmaceutical, and government scientists in basic research and clinical investigation. Key pharmaceutical, biotechnology, academic, and National Institutes of Health scientists presented overviews of their new agents and products in clinical development (representing the next generation of promising agents). Senior FDA physicians from the Center for Drugs and Center for Biologics presented on current standards for new drug and biologic approval for chemoprevention efficacy. Some of the key topics included recent advances in the state of knowledge of promising agents in the clinic based on molecular targets as well as bottlenecks in drug development for pharmaceutical sponsors; strategic modulable biomarkers that can serve as primary endpoints in phase 1/2 trials to assess preventive efficacy; high-risk cohorts with precancer (high-grade prostatic intraepithelial neoplasia) and representative clinical trial designs that are ready for immediate translation into efficient prevention trials, such as Bayesian sequential monitoring for early assessment of biologic activity and factorial designs for assessment of multiagent combinations. Finally, each expert panel generated recommendations for areas of future research emphasizing opportunities and infrastructure needs.
The marked discrepancy between the prevalence of preclinical prostate cancer and the incidence of clinically manifest disease indicates a long latency phase and significant heterogeneity in the progression potential of early neoplastic lesions. There are a variety of histologic changes within prostatic epithelium that have been termed atypical or dysplastic. The 2 most widely studied of these lesions are prostatic intraepithelial neoplasia (PIN) and atypical adenomatous hyperplasia (AAH). Although associations between AAH and adenocarcinoma are spurious, those linking high-grade PIN (HGPIN) to cancer are far more established. There is a significantly increased risk for patients with isolated HGPIN to have prostate cancer confirmed on subsequent biopsy, suggesting that HGPIN is a marker for prostate carcinoma in addition to its potential role as a premalignant lesion. Autopsy studies reveal that HGPIN is found in association with cancer in 63% to 94% of malignant and 25% to 43% of benign prostates. Data on age and race reveal that African American men develop more extensive HGPIN at a younger age than white men. A wide spectrum of molecular/genetic abnormalities appears to be common to both HGPIN and prostate cancer. Data loss of 8p, 10q, 16q, 18q, and gain of 7q31, 8q, multiple copies of the c-myc genes, along with changes in chromatin texture, telomerase activity, cell cycle status, and proliferative indices collectively suggest that HGPIN is intermediate between benign epithelium and prostatic carcinoma with respect to these markers. These data indicate that HGPIN is important in neoplastic progression, and may present an appropriate target/marker for chemoprevention.
A great deal of effort regarding the basic understanding and clinical relevance of the prevention of prostate cancer has emerged over the past decade. Chemoprevention or the administration of a drug or other agent in an attempt to prevent, inhibit, or delay the progression of localized prostate cancer has gained the most recent attention. Efforts have focused primarily in the identification of bioactive chemopreventive agents, risk factors identifying individuals with the highest likelihood of developing prostate cancer, pathologic identification of premalignant lesions, and epidemiologic studies to better understand the natural history of early prostate cancer. However, less work has been focused on identifying and characterizing our presently available biomarkers in an attempt to validate their use as surrogate endpoints or documenting their clinical utility in chemoprevention. This update will focus on a critical evaluation of prostate-specific antigen (PSA), percentage of free PSA, and human glandular kallikrein-2 (hK2) and how they may be used or misused for chemoprevention studies.
Needle biopsy of the prostate safely furnishes tissue that can be studied for the effects of promising chemopreventive agents on biomarkers. The modulation of biomarkers, such as those for apoptosis (TUNEL, Bcl-2, or nuclear morphometry), angiogenesis (factor 8), and cell proliferation (Ki-67), can indicate the potential of a new agent without waiting for the definitive evaluation of traditional endpoints, such as reduction in cancer mortality. A recent modification of prostate biopsy technique, including additional cores taken from the lateral peripheral zone, may improve the cancer yield by as much as 35% without increasing major complications, facilitating serial in vivo tests on cancer tissue. The serial biopsy approach may be especially valuable in "watchful waiting" cohorts.
OBJECTIVES: To develop an artificial neural network (ANN) model to predict lymph node (LN) spread in men with clinically localized prostate cancer and to describe a clinically useful method for interpreting the ANN's output scores. METHODS: A simple, feed-forward ANN was trained and validated using clinical and pathologic data from two institutions (n = 6135 and n = 319). The clinical stage, biopsy Gleason sum, and prostate-specific antigen level were the input parameters and the presence or absence of LN spread was the output parameter. Patients with similar ANN outputs were grouped and assumed to be part of a cohort. The prevalence of LN spread for each of these patient cohorts was plotted against the range of ANN outputs to create a risk curve. RESULTS: The area under the receiver operating characteristic curve for the first and second validation data sets was 0.81 and 0.77, respectively. At an ANN output cutoff of 0.3, the sensitivity achieved for each validation set was 63.8% and 44.4%; the specificity was 81.5% and 81.3%; the positive predictive value was 13.6% and 6.5%; and the negative predictive value was 98.0% and 98.1%, respectively. The risk curve showed a nearly linear increase (best fit R(2) = 0.972) in the prevalence of LN spread with increases in raw ANN output. CONCLUSIONS: The ANN's performance on the two validation data sets suggests a role for ANNs in the accurate clinical staging of patients with prostate cancer. The risk curve provides a clinically useful tool that can be used to give patients a realistic assessment of their risk of LN spread.
OBJECTIVES: Serum acid phosphatase (ACP) was once used as the marker for advanced prostate cancer. However, with the development of assays for prostate-specific antigen (PSA), a more sensitive and specific tumor marker, the use of ACP has diminished. We investigated the prognostic value of preoperative serum ACP in predicting prognosis for men with localized prostate cancer following radical retropubic prostatectomy (RRP). METHODS: Of 2293 men treated from 1982 to 1998, 1681 men had a preoperative ACP measurement using an enzymatic assay. We analyzed the actuarial freedom from biochemical (PSA) progression following RRP according to ACP levels. We used multivariate logistic regression and proportional hazards models to determine the independent prognostic value of ACP level with respect of pathologic stage and biochemical recurrence. RESULTS: ACP was not an independent predictor of organ confinement or lymph node involvement in the multivariate logistic regression models using preoperative variables. However, in the proportional hazards model, ACP was an independent predictor of tumor recurrence following RRP, and there was a statistically significant improvement in biochemical recurrence-free survival for men with lower levels of ACP (P <0.001). Furthermore, the normalized hazard ratios of ACP and PSA for predicting biochemical recurrence were similar. CONCLUSIONS: Stratification of men according to their preoperative ACP levels was predictive of patient outcome after RRP. Proportional hazards modeling using preoperative variables demonstrated that the serum ACP level is an independent predictor of tumor recurrence following RRP.
OBJECTIVES: To assess the diagnostic performance of complexed prostate-specific antigen (cPSA), total PSA (tPSA), and calculated free/total PSA (f/t PSA) ratios in the differentiation of benign disease from prostate cancer (CaP) using a contemporary patient cohort. METHODS: The cPSA, tPSA, and calculated fPSA values were determined using the Bayer Immuno-1 system. To validate our calculated f/t PSA ratio, we also retrospectively measured fPSA using the Abbott AxSYM immunoassay system in archival pretreatment sera obtained between 1990 and 1997 from 362 men with clinically and biopsy-confirmed benign prostatic hyperplasia (n = 179) or CaP (n = 183). The diagnostic utility of tPSA, cPSA, and the calculated f/t PSA ratio was assessed using a contemporary test population consisting of sera prospectively collected between June 1999 and June 2000 from 3006 men who had recently undergone a systematic biopsy by urologists in clinical practices throughout the United States. This contemporary patient sample had biopsy diagnoses of either no evidence of malignancy (n = 1857) or CaP (n = 1149). All serum samples had tPSA values between 2.0 and 20.0 ng/mL. RESULTS: The measured versus calculated f/t PSA ratios had a Pearson's correlation coefficient of 0.9130 in the retrospectively studied population of 362 men. The areas under the receiver operating characteristic curves (ROC-AUCs) for the measured and calculated f/t PSA ratios were indistinguishable (69.6% versus 69.2%, respectively). In the contemporary population (n = 3006), the ROC-AUC for tPSA, cPSA, and the calculated f/t PSA ratio was 52.2%, 53.9%, and 58.4%, respectively. We also compared the diagnostic performance using published cutoffs for tPSA (greater than 4.0 ng/mL), cPSA (greater than 3.8 ng/mL), and the f/t PSA ratio (greater than 15% and greater than 25%) in tPSA reflex ranges of 2 to 20 ng/mL and 2 to 10 ng/mL. We found that both cPSA and the f/t PSA ratio (greater than 25% cutoff) outperformed tPSA and yielded similar results in terms of biopsies spared and cancers missed. CONCLUSIONS: The calculated f/t PSA ratio and cPSA perform equally well in terms of the improvement of specificity in the discrimination of benign disease and CaP. The f/t PSA ratio and cPSA provide clinical benefits over the use of tPSA alone, such as an increased sparing of unnecessary biopsies performed with a manageable degree of risk of delayed cancer detection.
OBJECTIVES: To develop a model that will identify a contemporary cohort of patients at high risk of early prostate cancer recurrence (greater than 50% at 36 months) after radical retropubic prostatectomy for clinically localized disease. Data from this model will provide important information for patient selection and the design of prospective randomized trials of adjuvant therapies. METHODS: Proportional hazards regression analysis was applied to two patient cohorts to develop and cross-validate a multifactorial predictive model to identify men with the highest risk of early prostate cancer recurrence. The model and validation cohorts contained 904 and 901 men, respectively, who underwent radical retropubic prostatectomy at Johns Hopkins Hospital. This model was then externally validated using a cohort of patients from the Mayo Clinic. RESULTS: A model for weighted risk of recurrence was developed: R(W)'=lymph node involvement (0/1)x1.43+surgical margin status (0/1)x1.15+modified Gleason score (0 to 4)x0.71+seminal vesicle involvement (0/1)x0.51. Men with an R(W)' greater than 2.84 (9%) demonstrated a 50% biochemical recurrence rate (prostrate-specific antigen level greater than 0.2 ng/mL) at 3 years and thus were placed in the high-risk group. Kaplan-Meier analyses of biochemical recurrence-free survival demonstrated rapid deviation of the curves based on the R(W)'. This model was cross-validated in the second group of patients and performed with similar results. Furthermore, similar trends were apparent when the model was externally validated on patients treated at the Mayo Clinic. CONCLUSIONS: We have developed a multivariate Cox proportional hazards model that successfully stratifies patients on the basis of their risk of early prostate cancer recurrence.
OBJECTIVES: The decision to perform prostate biopsy has traditionally been based on an abnormal prostate-specific antigen (PSA) level or abnormal digital rectal examination (DRE) findings. For example, a 60-year-old man with a benign DRE and PSA level of 4.1 ng/mL would be counseled for biopsy, and the same man with a PSA level of 3.9 ng/mL might be counseled against biopsy. However, the difference in these PSA levels and in the likelihood of these two men having prostate cancer is not significant. We constructed a probability nomogram for the likelihood of detecting prostate cancer, thus aiding in the decision of whether to perform a prostate biopsy. METHODS: Using multivariate logistic regression analysis and data from 2054 men (mean age 64 years) participating in the Tyrol Screening Project between January 9, 1993 and January 9, 1997, patient age, PSA level, and DRE findings were analyzed for their ability to determine the likelihood of finding prostate cancer on transrectal ultrasound-guided biopsy. RESULTS: DRE was suspicious in 278 men (13.5%). Overall, 498 (24.5%) of 2054 men biopsied had prostate cancer. The probability of discovering cancer on biopsy was calculated using patient age, DRE findings, and PSA level. CONCLUSIONS: DRE status had a large influence on the likelihood of positive biopsy across all PSA and age ranges. A combination of PSA, DRE result, and age better defined the probability of a positive biopsy than any factor alone. Using this nomogram, the decision to proceed with or defer prostate biopsy can be based on an actual probability of discovering prostate cancer rather than a single PSA-based cutpoint. These data may aid physicians and patients in decision-making.
OBJECTIVES: To evaluate the influence of isolated, histologically identified capsular incision (CI) (exposure of benign or malignant glands to the inked surgical margin in the setting of organ-confined disease) on disease progression after anatomic radical retropubic prostatectomy (RRP) for clinically localized prostate cancer. METHODS: Between March 1993 and September 1999, 4747 men underwent RRP at the Johns Hopkins Hospital; 107 men (2.3%) were diagnosed with CI in otherwise organ-confined disease; 92 (86%) had at least 6 months (mean 30) of follow-up. We matched these CI cases (based on surgeon, age, clinical stage, final pathologic Gleason grade, and preoperative serum prostate-specific antigen level) one-for-one with controls in three additional pathologically defined groups and compared the freedom from disease progression (prostate-specific antigen level greater than 0.2 ng/mL and/or local palpable recurrence) after RRP. RESULTS: The actuarial 3-year likelihood of freedom from disease progression was 87.8% for the CI group, 96.4% for men with organ-confined disease (P = 0.10), 91.3% for men with extraprostatic extension and negative surgical margins (P = 0.99), and 73.9% for men with positive surgical margins resulting from extraprostatic extension (P <0.01). No statistically significant difference was found in the actuarial likelihood of freedom from disease progression between men with CI into benign glands (n = 22) and men with CI into tumor (n = 70) (P = 0.93). CONCLUSIONS: No statistically significant difference was found in the likelihood of early recurrence between patients with isolated CI and other specimen-confined disease. Patients with isolated CI have a significantly lower likelihood of early recurrence than patients with positive surgical margins due to extraprostatic extension, regardless of whether the CI is into benign glands or tumor. Long-term follow-up is necessary to confirm these findings.
OBJECTIVES: We previously presented nomograms combining preoperative serum prostate-specific antigen (PSA), clinical (TNM) stage, and biopsy Gleason score to provide the likelihood of various final pathologic stages at radical retropubic prostatectomy. The data for the original nomograms were collected from men treated between 1982 and 1996. During the past 10 years, the stage at presentation has shifted, with more men presenting with Stage T1c, Gleason score 5 to 6, and serum PSA levels less than 10.0 ng/mL. In this work, we update the "Partin Tables" with a more contemporary cohort of men treated since 1994 and with revised PSA and Gleason categories. METHODS: Multinomial log-linear regression analysis was used to estimate the likelihood of organ-confined disease, extraprostatic extension, seminal vesicle or lymph nodal status from the preoperative PSA stratified as 0 to 2.5, 2.6 to 4.0, 4.1 to 6.0, 6.1 to 10.0, and greater than 10 ng/mL, clinical (AJCC-TNM, 1992) stage (T1c, T2a, T2b, or T2c), and biopsy Gleason score stratified as 2 to 4, 5 to 6, 3 + 4 = 7, 4 + 3 = 7, or 8 to 10 among 5079 men treated with prostatectomy (without neoadjuvant therapy) between 1994 and 2000 at Johns Hopkins Hospital. The average age was 58 years. RESULTS: In this cohort, more than 60% had T1c, more than 75% had Gleason score of 6, more than 70% had PSA greater than 2.5 and less than 10.0 ng/mL, and more than 60% had organ-confined disease. Nomograms of the robust estimated likelihoods and 95% confidence intervals were developed from 1000 bootstrap analyses. The probability of organ-confined disease improved across the groups, and further stratification of the Gleason score and PSA level allowed better differentiation of individual patients. CONCLUSIONS: These updated "Partin Tables" were generated to reflect the trends in presentation and pathologic stage for men newly diagnosed with clinically localized prostate cancer at our institution. Clinicians can use these nomograms to counsel individual patients and help them make important decisions regarding their disease.
Pathologic stage is the most reliable means of predicting the likelihood of curable prostate cancer at the time of definitive treatment. Its prediction is of the greatest importance to individuals with clinically localized disease, principally because of the therapeutic and prognostic implications. Multivariate models integrating variables that can be derived from clinical and pathologic assessment have been shown to be reliable and useful in urologic practice. Among these variables, the combination of clinical stage, serum PSA, and biopsy Gleason score provides reliable assessment of the risk for extraprostatic disease that can be used readily for counseling individual patients. Other biopsy-derived parameters may contribute additional information, but their value in multivariate analysis has not been validated in a multi-institutional setting. The development of new prognostic markers is a priority objective in current research to distinguish patients in whom cancer cannot be controlled by surgical treatment. For patients undergoing radical prostatectomy, definitive pathologic stage certainly will remain an important prognostic factor; therefore, clinical practice will continue to be determined by its accurate prediction.
In a large series of 2404 men with a mean follow-up of 6.3 plus or minus 4.2 years (range, 1-17) after anatomic RRP for clinically localized prostate cancer, 412 men (17%) have recurred. A detectable PSA was the only evidence of recurrence in 9.7%, whereas 1.7% and 5.8% had local recurrence and distant metastasis, respectively. The overall actuarial 5-, 10-, and 15-year recurrence-free survival rates for these men were 84%, 74%, and 66%, respectively. As demonstrated in the authors' previous reports, the actuarial likelihood of a postoperative recurrence increased with advancing clinical stage, Gleason-score, preoperative PSA level, and pathologic stage. Subdivision of men with Gleason 7 tumors resulted in better stratification. There was a similar actuarial likelihood of postoperative recurrence for men with Gleason 4 + 3 and Gleason score 8 to 10 disease. The actuarial rate of recurrence of tumor for men with Gleason 3 + 4 disease was statistically different from the rate for men with Gleason score 6 or Gleason 4 + 3 disease. The overall actuarial metastasis-free survival rates at 5, 10, and 15 years were 96%, 90%, and 82%, respectively. The overall actuarial cancer-specific survival rates at 5, 10, and 15 years were 99%, 96%, and 90%, respectively. This study provides long-term outcome of patients with clinically localized cancer who underwent RRP between 1982 and 1999. Recognizing that this long-term study includes many patients with more advanced disease diagnosed before the PSA era, caution must be exercised in comparing these results with the outcomes for cohorts of patients treated since 1989. Anatomic RRP is an effective way to manage clinically localized prostate cancer. Excellent long-term results can be obtained with RRP for early stage disease. The proportion of men with early stage prostate cancer will continue to increase with wide use of serum PSA testing and digital rectal examination.