PREDICTING PROSTATE SPECIFIC ANTIGEN OUTCOME PREOPERATIVELY IN THE PROSTATE SPECIFIC ANTIGEN ERA

PURPOSE: We evaluated the ability of previously defined risk groups to predict prostate specific antigen (PSA) outcome 10 years after radical prostatectomy in patients diagnosed with clinically localized prostate cancer during the PSA era. MATERIALS AND METHODS: Between 1989 and 2000, 2,127 men with clinically localized prostate cancer underwent radical prostatectomy, including 1,027 at Hospital of the University of Pennsylvania (study cohort) and 1,100 at Brigham and Women's Hospital (validation cohort). Cox regression analysis was done to calculate the relative risk of PSA failure with the 95% confidence interval (CI) in patients at intermediate and high versus low risk. The Kaplan-Meier actuarial method was used to estimate PSA outcome 10 years after radical prostatectomy. RESULTS: Compared with low risk patients (stages T1c to 2a disease, PSA 10 ng./ml. or less and Gleason score 6 or less) the relative risk of PSA failure in those at intermediate (stage T2b disease or PSA greater than 10 to 20 ng./ml. or less, or Gleason score 7) and high (stage T2c disease, or PSA greater than 20 ng./ml. or Gleason score 8 or greater) risk was 3.8 (95% CI 2.6 to 5.7) and 9.6 (95% CI 6.6 to 13.9) in the study cohort, and 3.3 (95% CI 2.3 to 4.8) and 6.3 (95% CI 4.3 to 9.4) in the validation cohort. The 10-year PSA failure-free survival rate in the 1,020 patients in the low, 693 in the intermediate and 414 in the high risk groups was 83%, 46% and 29%, respectively (p <0.0001). CONCLUSIONS: Based on 10-year actuarial estimates of PSA outcome after radical prostatectomy 3 groups of patients were identified using preoperative PSA, biopsy Gleason score and 1992 clinical T category.     

The extent of biopsy involvement as an independent predictor of extraprostatic extension and surgical margin status in low risk prostate cancer: implications for treatment selection

PURPOSE: We identify predictors of extraprostatic extension and positive surgical margins in patients with low risk prostate cancer (prostate specific antigen [PSA] 10 ng./ml. or less, biopsy Gleason score 7 or less and clinical stage T1c-2b). MATERIALS AND METHODS: From August 1997 to January 1999, 143 previously untreated patients underwent radical retropubic prostatectomy for clinically localized prostate cancer. A total of 62 patients were low risk, with PSA 10 ng./ml. or less, biopsy Gleason score 7 or less and clinical stage T1c-2b, and had sextant biopsy with separate pathological evaluation of each sextant cores. PSA, clinical stage, biopsy Gleason score, average percentage of cancer in the entire biopsy specimen, maximum percentage of cancer on the most involved core, number of cores involved and bilaterality were evaluated for association with extraprostatic extension, seminal vesicle involvement and positive surgical margins. RESULTS: Of the 62 patients 13 (21%) had extraprostatic extension, 6 (10%) seminal vesicle involvement and 20 (32%) positive surgical margins. Average percentage greater than 10% and maximum percentage greater than 25% were associated with extraprostatic extension (p = 0.01 and 0.004, respectively). Average percentage greater than 10%, maximum percentage greater than 25%, more than 2 cores involved and bilaterality were associated with positive surgical margins (p = 0.007, 0.01, 0.002 and 0.03, respectively). On multivariate analysis maximum percentage remained the only independent predictor of extraprostatic extension (p = 0.03), and the number of cores involved remained an independent predictor of positive surgical margins (p = 0.01). Biopsy Gleason score, PSA and clinical stage did not correlate with extraprostatic extension or positive surgical margins in this patient population. CONCLUSIONS: In low risk prostate cancer the extent of biopsy involvement significantly correlates with the risk of extraprostatic extension and positive surgical margins. Biopsy information should be considered when selecting and modifying treatment modalities.     

Predicting recurrence after radical prostatectomy for patients with high risk prostate cancer

PURPOSE: Previous studies have shown that patients with clinical stage T2c-T3 prostate cancer, serum prostate specific antigen (PSA) at diagnosis greater than 20 ng./ml. or a biopsy Gleason score of 8 to 10 are at high risk for disease recurrence after radical prostatectomy. We determined the most important pretreatment predictors of disease recurrence in this high risk population. MATERIALS AND METHODS: We identified 547 patients with high risk prostate cancer who underwent radical prostatectomy at University of California, San Francisco or as part of the Cancer of the Prostate Strategic Urological Research Endeavor data base, a longitudinal disease registry of patients with prostate cancer. High risk disease was defined as 1992 American Joint Committee on Cancer clinical stage T2c-T3 disease in 411 patients, serum PSA at diagnosis greater than 20 ng./ml. in 124 and/or biopsy Gleason score 8 to 10 in 114. Disease recurrence was defined as PSA 0.2 ng./ml. or greater on 2 consecutive occasions after radical prostatectomy or second cancer treatment more than 6 months after surgery. The Cox proportional hazards analysis was performed to determine significant independent predictors of disease recurrence. The likelihood of disease recurrence for clinically relevant patient groups was determined using the Kaplan-Meier method and compared using the log rank test. RESULTS: Median followup after surgery was 3.1 years. Disease recurred in 177 patients (32%). Multivariate analysis demonstrated that serum PSA at diagnosis, biopsy Gleason score, ethnicity and the percent of positive prostate biopsies were significant independent predictors of disease recurrence, while patient age and clinical tumor stage were not. Patients with a Gleason score 8 to 10 tumor and a serum PSA of 10 ng./ml. or less had a significantly higher likelihood of remaining disease-free 5 years after surgery than those with PSA greater than 10 ng./ml. (47% versus 19%, p <0.05). Patients with a serum PSA at diagnosis of greater than 20 ng./ml. and a Gleason score of less than 8 had a significantly higher likelihood of remaining disease-free 5 years after surgery than similar patients with a Gleason score of 8 or greater (45% versus 0%, p <0.05). CONCLUSIONS: PSA, Gleason score, ethnicity and the percent of positive prostate biopsies appear to be the most important pretreatment predictors of disease recurrence in men with high risk prostate cancer. Patients with high grade disease may continue to be appropriate candidates for local therapy if PSA is less than 10 ng./ml. at diagnosis or there are fewer than 66% positive prostate biopsies.     

Lower prostate specific antigen outcome than expected following radical prostatectomy in patients with high grade prostate and a prostatic specific antigen level of 4 ng/ml. Or less

PURPOSE: We report the estimates of 10-year prostate specific antigen (PSA) outcome following radical prostatectomy in patients with or without grade 4 or 5 disease in the needle biopsy or prostatectomy specimen stratified by the presenting PSA level. MATERIALS AND METHODS: From 1989 to 2001, 2,254 patients treated with radical prostatectomy for clinically localized prostate cancer comprised the study cohort. PSA outcome was estimated using the actuarial method of Kaplan and Meier, and was stratified by the presenting PSA level and needle biopsy and prostatectomy Gleason score. RESULTS: The 10-year estimates of PSA outcome declined significantly (p 相似文献   

Biochemical and pathological predictors of the recurrence of prostatic adenocarcinoma with seminal vesicle invasion

PURPOSE: We assessed biochemical and pathological factors as predictors of recurrence in men with seminal vesicle invasion. MATERIALS AND METHODS: A consecutive series of 812 men who underwent radical retropubic prostatectomy between 1992 and 2000 included 106 (13%) with seminal vesicle invasion. Disease recurrence was defined as prostate specific antigen (PSA) 0.4 ng./ml. or greater. Patients with less than 12 months of followup, salvage radical retropubic prostatectomy, lymph node metastases and adjuvant therapy were excluded from study. Data on the remaining 66 cases were analyzed using the chi-square test, bivariate logistic regression, Kaplan-Meier analyses and Cox proportional regression. Variables included demographics, recurrence, time from surgery to recurrence, positive margins, capsular invasion, extracapsular extension, Gleason score (2 to 6, 7 and 8 to 10), and dichotomized values of preoperative PSA (10 or less versus 10 ng./ml.) and tumor volume (20% or less versus greater than 20%). RESULTS: Mean patient age was 62 years (range 48 to 74). At an average followup of 47.7 months (range 13 to 109) 53% of the patients were free of biochemical recurrence. Mean time to recurrence was 18.6 months (range 1.7 to 51.6). Univariate analyses revealed a statistical significant increased risk of recurrence in patients with PSA greater than 10 ng./ml. (p <0.0001), capsular invasion (p = 0.01) and age (p = 0.036). When adjusting for potential covariates, Cox proportional regression analysis indicated that higher PSA (hazard ratio 7.33, 95% CI 2.57 to 20.95), larger tumor volume (hazard ratio 5.64, 95% CI 1.97 to 16.19) and higher age (hazard ratio 1.13, 95% CI 1.04 to 1.22) were significantly associated with shorter time to recurrence. CONCLUSIONS: PSA greater than 10 ng./ml., tumor volume greater than 20% and age are significant predictors of recurrence after radical retropubic prostatectomy in patients with prostate cancer and seminal vesicle invasion. Hopefully future randomized trials may show a survival benefit of adjuvant therapy in patients at high risk.     

LACK OF ASSOCIATION OF PROSTATE CARCINOMA NUCLEAR GRADING WITH PROSTATE SPECIFIC ANTIGEN RECURRENCE AFTER RADICAL PROSTATECTOMY

PURPOSE: Grading prostate cancer using the Gleason system relies only on architectural tumor growth, in contrast to other systems, such as the WHO system, which grade prostate carcinoma based on nuclear features as well as architectural patterns. The prognostic significance of nuclear grading remains controversial since most studies were performed before prostate specific antigen (PSA) screening became widely available. We evaluated the significance of nuclear grade for predicting PSA recurrence in a contemporary cohort of patients treated with radical prostatectomy for clinically localized prostate carcinoma. MATERIALS AND METHODS: Nuclear grades 1 to 3 were determined in 141 consecutive radical prostatectomies in 1995. Predominant and worst nuclear grade was determined by a consensus of 3 pathologists. Statistical analysis compared nuclear grade with Gleason score using the chi-square test. The Cox proportional hazards analysis was performed to calculate the ability of nuclear grade, Gleason score and other variables to predict PSA recurrence. RESULTS: We identified a significant association of Gleason score with worst nuclear grade (p = 0.007). All 6 cases with a Gleason score of 8 or greater had a worst nuclear grade of 3, in contrast to 36 of 60 (60%) with a score 6 or less, in which the worst nuclear grade was 3. Of the 141 patients 31 (21.9%) had PSA recurrence at a median followup of 3.7 years. The univariate Cox model revealed significant associations of PSA recurrence with Gleason score 8 or greater (hazards ratio 5.5, p = 0.005), extraprostatic extension (hazards ratio 3.4, p = 0.001), positive surgical margin (hazards ratio 2.6, p = 0.009), seminal vesicle involvement (hazards ratio 7.3, p <0.001), preoperative serum PSA (hazards ratio 1.03, p = 0.007), tumor stage (hazards ratio 3.6, p = 0.001) and maximal tumor dimension (hazards ratio 2.4, p <0.001). However, overall and worst nuclear grade did not predict PSA recurrence (p = 0.89 and 0.13, respectively). Nuclear grade did not fit any multivariate model tested, which otherwise included Gleason score, log(PSA), surgical margin status, extraprostatic extension, seminal vesicle status, tumor size and pathological stage. By varying sample fixation time we also showed that benign prostate tissue in the same section as prostate carcinoma had grade 2 or 3 nuclear changes, that is moderate to marked anaplasia. CONCLUSIONS: High nuclear grade is associated with high Gleason score. However, prostate carcinoma with a Gleason score of 6 or less shows extreme variability. Nuclear grade determined by light microscopy failed to predict PSA recurrence in a contemporary series of men with clinically localized prostate cancer treated with radical prostatectomy. Nuclear morphology is subject to tissue fixation and processing artifact. Any nuclear morphometric study must consider this artifact.     

PREDICTION OF POST-RADICAL PROSTATECTOMY PATHOLOGICAL OUTCOME FOR STAGE T1c PROSTATE CANCER WITH PERCENT FREE PROSTATE SPECIFIC ANTIGEN: A PROSPECTIVE MULTICENTER CLINICAL TRIAL

PURPOSE: Prostate specific antigen (PSA) exists in bound (complexed) and unbound (free) forms in serum. The percentage of free PSA enhances the specificity of PSA testing for prostate cancer detection. We evaluated the use of percent free PSA preoperatively to predict pathological stage. MATERIALS AND METHODS: A total of 379 men with prostate cancer and 394 with benign prostatic disease 50 to 75 years old were enrolled in this prospective study at 7 medical centers. All subjects had a palpably benign prostate gland, serum PSA 4.0 to 10.0 ng./ml. and a histologically confirmed diagnosis. The Hybritech Tandem PSA and free PSA assays were used. Of the 379 cancer patients 268 (71%) underwent radical prostatectomy. RESULTS: Higher percent free PSA levels were associated with more favorable histopathological findings in prostatectomy specimens. A value of 15% free PSA provided the greatest discrimination in predicting favorable pathological outcome. Organ confined cancer, Gleason sum less than 7 and small tumors (10% or less involvement of the prostate) were noted in 75% of patients with greater than 15% and only 34% with 15% or less free PSA (p<0.001). Multivariate logistic regression analysis revealed percent free PSA to be the strongest predictor of postoperative pathological outcome (odds ratio 2.25), followed by biopsy Gleason sum (2.06) and patient age (1.35). Total PSA was not predictive in this cohort but has been shown in prior studies to be predictive of outcome when a broader range of PSA values is evaluated. CONCLUSIONS: Percent free PSA may be used for risk assessment of the presence (diagnosis) and stage of prostate cancer in men with PSA between 4 and 10 ng./ml. Percent free PSA may be combined with PSA, digital rectal examination and biopsy findings to help predict postoperative pathological stage and grade, and may assist the patient and physician in making more informed treatment decisions.     

Preoperative serum prostate specific antigen levels between 2 and 22 ng./ml. correlate poorly with post-radical prostatectomy cancer morphology: prostate specific antigen cure rates appear constant between 2 and 9 ng./ml.

PURPOSE: Serum prostate specific antigen (PSA) is widely used as a guide to initiate prostatic biopsies and to follow men older than 50 years old with and without prostate cancer. However, benign prostatic hyperplasia (BPH) is a common cause of serum PSA values between 2 and 10 ng./ml. A better understanding of the relationships among serum PSA, prostate cancer and BPH is important. MATERIALS AND METHODS: A total of 875 men underwent radical prostatectomy at our institution between December 1984 and January 1997. Of these men 784 had a serum PSA of 2 to 22 ng./ml., including 579 with the largest cancer located in the peripheral zone of the prostate. Of the 579 men 406 had serum PSA followups for greater than 3 years after radical prostatectomy. We examined Pearson correlations (R2) between preoperative serum PSA, and the volume of Gleason grades 4/5 and 3 to 1 cancer in 784 men, separating peripheral zone from transition zone cancers. We used broken line regression with break points of 7 and 9 ng./ml. preoperative PSA to summarize the relationship of each PSA doubling to 5 different morphological variables in 579 men with peripheral zone cancer. A 9 ng./ml. break point was used for prostate weight. Trend summaries with a local regression line for the relationships between 6 morphological variables and PSA were superimposed on full scatterplots of the 579 men with PSA less than 22 ng./ml. Cox proportional hazard models were used to examine 5-year PSA failure-free probabilities based on 406 men with minimal PSA followups greater than 3 years at break points of 7 to 9 ng./ml. PSA. RESULTS: Pearson correlation between cancer volume and preoperative serum PSA in 875 men was weak (r2 = 0.27) and driven by large cancers with serum PSA greater than 22 ng./ml. For peripheral zone cancer the overall R2 x 100 for 641 men with low and high grade cancer was 10% and only 3% for low grade cancer, that is almost no PSA produced by these peripheral zone cancers enters the serum. All morphological variables changed at rates of doubtful medical significance below a PSA of 7 to 9 ng./ml. but at rates that were significantly worse above 9 ng./ml. R2 for these relationships was never greater than 15%. Large individual morphological variations at all levels of PSA emphasize the serious limitation of PSA as a predictor of prostate cancer morphology. Below 9 ng./ml. prostate weight increased by 21% for each doubling of PSA but above 9 ng./ml. the increase was only 4.8%. CONCLUSIONS: Preoperative serum PSA has a clinically useless relationship with cancer volume and grade in radical prostatectomy specimens, and a limited relationship with PSA cure rates at preoperative serum PSA levels of 2 to 9 ng./ml. Trend summaries for prostate weight on broken line regression showed that below 9 ng./ml. BPH is a strong contender for the cause of PSA elevation, constituting the primary cause of the over diagnosis of prostate cancer.     

Pathological features of Gleason score 6 prostate cancers in the low and intermediate range of prostate‐specific antigen level: is there a difference?

OBJECTIVE

To assess the pathological features of Gleason score 6 prostate cancers after radical prostatectomy in the low (<4 ng/mL) and intermediate range of prostate‐specific antigen level (4–10 ng/mL), as such prostate cancers are considered to be well differentiated tumours with a low risk for recurrence after therapy.

PATIENTS AND METHODS

In all, 1354 patients with T1c prostate cancer and PSA levels of <10.0 ng/mL had a radical retropubic prostatectomy. Patients with Gleason score 6 tumours were divided into two groups, those with PSA levels of <4 and 4.0–10.0 ng/mL. Extracapsular extension, positive surgical margins, biochemical recurrence (BCR) and mean time to BCR were evaluated.

RESULTS

Of the 1354 patients, there were 437 (32.3%) with Gleason score 6 prostate cancers. Patients in the low PSA group had less extraprostatic disease than those with a higher level (5.9% vs 14.5%) and both groups had an almost equal proportion of positive surgical margins (9.4% vs 11.0%). In the low PSA group there was statistically significantly shorter BCR than in the high PSA group, with a mean time to BCR of 1.7 vs 3.1 years.

CONCLUSIONS

These results show a statistically significantly higher rate of extraprostatic disease and earlier BCR in men with a high than a low PSA level even in Gleason score 6 prostate cancer. As the rate of BCR and extracapsular extension are significantly related to prostate cancer mortality, these findings further support the concept of screening using low PSA levels.     

Under staging and under grading in a contemporary series of patients undergoing radical prostatectomy: results from the Cancer of the Prostate Strategic Urologic Research Endeavor database

PURPOSE: We determined the prevalence of under staging and under grading in contemporary patients undergoing radical prostatectomy in academic and community based urology practices, and defined important predictors of under staging in this population. MATERIALS AND METHODS: We compared clinical T stage and biopsy Gleason score with pathological T stage and prostatectomy Gleason score in 1,313 patients enrolled in the Cancer of the Prostate Strategic Urologic Research Endeavor database, a longitudinal registry of patients with prostate cancer, who underwent radical prostatectomy, including 53% since 1995. Under grading was determined for the primary and secondary Gleason patterns and defined as a biopsy Gleason pattern of 1 to 3 that became pathological Gleason pattern 4 or 5. Under staging was defined as a clinically organ confined tumor that was extraprostatic stages pT3 to 4 or N+ at radical prostatectomy. Univariate and multivariate analysis was performed to determine important risk factors for under staging and significant risk factors were used to identify the likelihood of under staging in clinically relevant patient subgroups. The importance of the percent of positive biopsies in regard to the likelihood of under staging was determined by assigning patients to previously described risk groups based on serum prostate specific antigen (PSA) at diagnosis and biopsy Gleason score. RESULTS: Under grading of primary and secondary Gleason patterns occurred in 13% and 29% of patients, respectively, while under staging occurred in 24%. Univariate and multivariate analysis revealed that PSA at diagnosis, biopsy Gleason score and the percent of positive biopsies were significant predictors of under staging. The percent of positive biopsies appeared to be most important for predicting the likelihood of extraprostatic disease extension in intermediate or high risk disease based on serum PSA at diagnosis and biopsy Gleason grade. CONCLUSIONS: The prevalence of under grading and under staging in contemporary patients undergoing radical prostatectomy may be lower than previously reported. PSA at diagnosis, biopsy Gleason score and the percent of positive biopsies are important predictors of under staging. The percent of positive biopsies should be incorporated into risk assessment models of newly diagnosed prostate cancer.     

The positive yield of imaging studies in the evaluation of men with newly diagnosed prostate cancer: a population based analysis

PURPOSE: We determine the positive yield of imaging studies performed on men with newly diagnosed prostate cancer. MATERIALS AND METHODS: A prospective, population based survey was conducted on 3,690 men with prostate cancer diagnosed between October 1, 1994 and October 31, 1995. Cases were identified by the rapid case ascertainment systems used in 6 geographic regions participating in the Surveillance, Epidemiology and End Results Program. Based on information captured in primary medical record reviews we estimated the positive yield of bone scans, computerized tomography (CT) and magnetic resonance imaging. RESULTS: The positive yield of bone scan and CT was less than 5% and 12%, respectively, for all men with prostate specific antigen (PSA) 4 to 20 ng./ml., and less than 2% and 9%, respectively, for those who also had a Gleason score of 6 or less. Only men with PSA greater than 50 ng./ml. and those with Gleason scores 8 to 10 and PSA greater than 20 ng./ml. had positive yields greater than 10% and 20% for bone scan and CT, respectively. CONCLUSIONS: Imaging studies designed to identify metastases and/or extracapsular extension in men with newly diagnosed prostate cancer frequently have a low positive yield. Wide variations exist in the use of imaging studies and are associated with tumor factors, such as Gleason score and serum PSA, and nontumor factors, such as state of residence. More extensive cost-effectiveness analyses are needed to define appropriate guidelines for ordering imaging studies to optimize the positive yield among men with newly diagnosed prostate cancer.     

Predicting the probability of significant prostate cancer in Japanese men with serum prostate‐specific antigen less than 10 ng/mL: Development of a novel pre‐biopsy nomogram

Objectives: To develop and assess a new nomogram incorporating pre‐biopsy clinical data to predict significant prostate cancer in Japanese men with a serum prostate‐specific antigen (PSA) level of less than 10 ng/mL. Methods: We collected pre‐biopsy data from 620 men with a serum total PSA of less than 10 ng/mL. They included 491 men with a negative biopsy and 129 men who were confirmed to have histological prostate cancer and subsequently underwent radical prostatectomy. Clinically significant tumors were defined as those with a tumor volume larger than 0.5 mL and/or a Gleason score of 7 or more. Results: One hundred and seven prostatectomy patients had clinically significant cancers. Stepwise multivariate logistic regression analysis showed that digital rectal examination findings, PSA adjusted for transition zone volume and free‐to‐total PSA ratio were the significant independent predictors of significant cancers (P < 0.0001). Using these pre‐biopsy independent factors, a nomogram was developed to predict significant cancers. According to a receiver operating characteristics analysis, the nomogram showed an area under the curve of 0.831. Conclusion: This represents the first nomogram to predict the probability of clinically significant cancers before biopsy. This tool is most likely to be useful in the management of patients with moderate to elevated PSA.     

Prospective detection of clinically relevant prostate cancer in the prostate specific antigen range 1 to 3 ng./ml. combined with free-to-total ratio 20% or less: the Aarau experience

PURPOSE: Little is known about the incidence rate and clinical relevance of prostate cancer in a low prostate specific antigen (PSA) level. In a prospective PSA based screening study we investigated the incidence and clinicopathological features of prostate cancer that occurred within PSA range 1 to 3 ng./ml. when the free-to-total ratio was 0.20 or less. MATERIALS AND METHODS: Men participating in the Aarau, Switzerland, section of the European Randomized Study of Screening for Prostate Cancer between October 1998 and July 2000 were included in the study. As a side study, all men with PSA between 1 and 3 ng./ml. and free-to-total ratio 0.20 or less were invited to undergo further evaluation with ultrasound guided sextant prostate biopsy. RESULTS: Overall, 168 (7.8%) participants fulfilled inclusion criteria. A total of 158 (94%) patients underwent prostate biopsy, and prostate cancer was detected in 17 (10.8%). There were no statistically significant differences between prostate cancer and benign prostatic hyperplasia in regard to patient age (60.7 versus 59.8 years), prostate volume (23.9 versus 23.0 cc), PSA (1.98 versus 1.86 ng./ml.), free-to-total ratio (0.161 versus 0.160), PSA density (0.089 versus 0.076 ng./ml.) or PSA transition zone density (0.33 versus 0.24 ng./ml., respectively). Median Gleason score was 5 on prostate biopsy versus 6 on retropubic prostatectomy specimen. Of the 14 patients who underwent surgery there were positive lymph nodes in 1, stage pT3b Gleason 7 disease in 1, and pathologically organ confined Gleason 5 in 2, Gleason 6 in 5 and Gleason 7 in 5. Mean tumor volume was 1.01 cc (range 0.02 to 5.17). There were 2 (14.3%) insignificant (less than 0.2 cc, Gleason grade 3 or less), 1 (7.1%) minimal (less than 0.5cc, Gleason grade 3 or less) and 11 (78.6%) clinically relevant and potentially harmful cancers. CONCLUSIONS: There is a significant number of prostate cancer cases diagnosed at PSA as low as 1 to 3 ng./ml. A majority of these tumors are clinically significant. This free-to-total ratio range may be helpful for identifying prostate cancer. The "window of opportunity" for detection of curable cancer may change in populations with higher life expectancy towards lower PSA. Lack of specificity and characterization of tumor aggressiveness remains an unsolved issue for PSA.     

PROSTATE SPECIFIC ANTIGEN VARIATION IN PATIENTS WITHOUT CLINICALLY EVIDENT PROSTATE CANCER

PURPOSE: We address long-term within individual variation of serum prostate specific antigen (PSA) in men without clinical or biopsy evidence of prostate cancer. MATERIALS AND METHODS: We studied 943 men from a prostate cancer screening program with 2 PSA (PSA1 and PSA2) measurements available. A third PSA (PSA3) was obtained from 571 men. Only participants with no clinical evidence of cancer were included in the study. Within individual PSA variability was calculated based on indexes of percent coefficient of variation, ratio difference and PSA velocity. The relationship among these indexes, interval between measurements and number of PSA samples was assessed. RESULTS: Mean interval was 670.4 days between PSA1 and PSA2, and 801.8 days between PSA2 and PSA3 (p<0.001). Mean coefficient of variation was 18% after 2 and 15.7% after 3 PSA measurements. Mean ratio differences were -0.047 ng./ml. for 2 and 0.033 ng./ml. for 3 samples. Mean PSA velocity was -0.128 ng./ml. per year for 2 and -0.055 ng./ml. per year for 3 samples, with 95% confidence intervals of 0.634 and 0.315, respectively. Variability was higher if only 2 PSA measurements were done (p<0.001). No clear relationship was found between individual variability and interval between measurements. CONCLUSIONS: PSA velocity is within normal limits in almost all men (more than 95%) without clinically relevant prostate cancer. PSA individual variability is not fully dependent on the time between measurements when intervals are long, and can be substantially decreased with a third PSA sample.     

Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis

PURPOSE: Lymphadenectomy for prostate cancer is limited to obturator and external iliac lymph nodes, although the internal lymph nodes represent the primary landing zone of lymphatic drainage. We performed anatomically adequate extended pelvic lymphadenectomy to assess the incidence of lymph node metastasis in cases of clinically localized prostate cancer. MATERIALS AND METHODS: A total of 103 consecutive patients underwent extended pelvic lymphadenectomy at radical retropubic prostatectomy comprising 9 selective fields, namely the external iliac, internal iliac, obturator and common iliac lymph nodes bilaterally, and the presacral lymph nodes. Histopathological findings were compared with serum prostate specific antigen (PSA), histopathological stage, preoperative biopsy and postoperative prostatectomy Gleason score. Extended pelvic lymphadenectomy was compared with radical retropubic prostatectomy and standard lymphadenectomy in 100 consecutive patients in terms of complications, the number of lymph nodes dissected and operative time. RESULTS: There were no significant differences in age, preoperative PSA or mean biopsy Gleason score in patients who underwent extended pelvic and standard lymphadenectomy. Metastases were diagnosed in 27 of the 103 patients (26.2%) who underwent the extended procedure. A mean of 28 lymph nodes (range 21 to 42) were dissected. Metastases were identified in the internal iliac and presacral regions despite negative obturator lymph nodes. Of the 27 patients 1 to 3 lymph nodes involved with metastasis were detected in 15, 9 and 1, respectively. In 26 of the 27 patients (95.8%) with lymph node metastasis PSA was greater than 10.5 ng./ml. and preoperative biopsy Gleason sum was 7 or greater. A low risk of 2% for lymph node disease was noted in patients with serum PSA less than 10.5 ng./ml. and biopsy Gleason sum less than 7. There were no significant differences in regard to intraoperative and postoperative complications, lymphocele formation or blood loss in the 2 groups. CONCLUSIONS: Extended pelvic lymphadenectomy is associated with a high rate of lymph node metastasis outside of the fields of standard lymphadenectomy in cases of clinically localized prostate cancer. Lymphadenectomy including the internal iliac lymph nodes should be performed in all patients with prostate cancer who are at high risk for lymph node involvement, as indicated by PSA greater than 10.5 ng./ml. and biopsy Gleason sum 7 or greater. In the low risk group pelvic lymphadenectomy can be omitted.     

Prediction of extraprostatic extension by prostate specific antigen velocity, endorectal MRI, and biopsy Gleason score in clinically localized prostate cancer

Objectives:   To investigate the clinical value of prostate specific antigen velocity (PSAV) in predicting the extraprostatic extension of clinically localized prostate cancer.
Methods:   One hundred and three patients who underwent radical prostatectomy for clinically localized prostate cancer were included in the analysis. The correlation between preoperative parameters, including PSA-based parameters, clinical stage, and histological biopsy findings, and the pathological findings were analyzed. Logistic regression analysis was performed to identify a significant set of independent predictors for the local extent of the disease.
Results:   Sixty-four (60.2%) patients had organ confined prostate cancer and 39 (39.8%) patients had extraprostatic cancer. The biopsy Gleason score, PSA, PSA density, PSA density of the transition zone, and PSAV were significantly higher in the patients with extraprostatic cancer than in those with organ confined cancer. Multivariate logistic regression analysis indicated that the biopsy Gleason score, endorectal magnetic resonance imaging findings, and PSAV were significant predictors of extraprostatic cancer ( P  < 0.01). Probability curves for extraprostatic cancer were generated using these three preoperative parameters.
Conclusions:   The combination of PSAV, endorectal magnetic resonance imaging findings, and biopsy Gleason score can provide additional information for selecting appropriate candidates for radical prostatectomy.     

Role of radical prostatectomy in patients with prostate cancer of high Gleason score

BACKGROUND: The routine use of serum prostate-specific antigen (PSA) testing combined with digital rectal examination has lowered tumor volume and clinical-pathological stage of men undergoing radical prostatectomy. Therefore, we may identify more men with poorly differentiated tumors of early clinical stage. In order to identify those who may benefit from radical prostatectomy, we evaluated known prognostic variables in patients with prostate cancer of high Gleason score (8-10). METHODS: Of 652 patients who underwent a radical prostatectomy as monotherapy for clinically localized prostate cancer between March 1991-December 1995, 84 patients with prostatectomy specimen Gleason score 8-10 tumors were identified. Clinical-pathological data were obtained from our prostate cancer database. Gleason score, PSA level, margin status, pathologic stage, and tumor volume were analyzed as general prognostic variables for disease-free survival (DFS). Follow-up ranged from 13-84 months (median, 36.2). Biochemical recurrence was defined as a postoperative PSA elevation greater than 0.4 ng/ml. RESULTS: The DFS for patients with Gleason score 8-10 and pathologically organ-confined disease was 62.5%. DFS was 56.2% for patients with PSA < or =10 ng/ml, compared to 19.2% for patients with serum PSA >10 ng/ml (P = 0.009). Patients with nonspecimen-confined disease (positive margins) had a DFS rate of 26.6% vs. 55% for patients with specimen-confined disease (negative margins) (P = 0.009). On multivariable analysis, only preoperative PSA < or =10 ng/ml (P = 0.02) and surgical margin status (P = 0.04) were significant predictors of DFS. CONCLUSIONS: Surgical margin status and preoperative serum PSA level are independent predictors of DFS for patients with high Gleason score prostate cancer treated by radical prostatectomy as monotherapy. Patients with poorly differentiated prostate cancer treated surgically at an early stage can have a favorable prognosis, especially if negative surgical margins are obtained. A preoperative serum PSA level < or =10 ng/ml carries the greatest likelihood of achieving prolonged DFS in this group of patients.     

Pretreatment predictors of time to cancer specific death after prostate specific antigen failure

PURPOSE: Whether pretreatment factors that predict for time to prostate specific antigen (PSA) failure also predict for time to prostate cancer specific death after PSA failure for patients with competing causes of mortality treated during the PSA era was the subject of this study. MATERIALS AND METHODS: Of 415 men with a median age of 73 years who underwent external beam radiation therapy between 1988 and 2001 for clinically localized prostate cancer 160 (39%) experienced PSA failure and 96 (23%) died. In 46 men (48%) the cause of death was prostate cancer. Cox regression multivariable analyses (multivariable analysis) were performed to evaluate the ability of the pretreatment PSA and centrally reviewed biopsy Gleason score to predict time to prostate cancer specific death after PSA failure. RESULTS: When analyzed as categorical variables using multivariable analysis, biopsy Gleason score 4 + 3 (p = 0.02), 8 to 10 (p = 0.02) disease and a pretreatment PSA greater than 20 ng./ml. (p = 0.03) were significant predictors of time to prostate cancer specific death after PSA failure. Estimates of prostate cancer specific death 5 years after PSA failure were 24%, 40% and 59% (p = 0.01) for patients with a biopsy Gleason score < or = 6, 3 + 4, 4 + 3 or higher and 22%, 40% and 60% (p = 0.04) for patients with a pretreatment PSA of 10 or less, greater than 10 and 20 or less, or greater than 20 ng./ml., respectively. CONCLUSIONS: Patients at high risk for PSA failure after radiation therapy based on pretreatment PSA greater than 20 ng./ml. or biopsy Gleason score 4 + 3 or greater are also at high risk for death from prostate cancer after PSA failure despite competing causes of mortality.     

Prostate cancer detection at low prostate specific antigen

PURPOSE: At low prostate specific antigen (PSA) the indication for prostate biopsy is usually an abnormal digital rectal examination. We evaluate the diagnostic value of PSA, digital rectal examination, transrectal ultrasonography and tumor characteristics at low PSA (0 to 4.0 ng./ml.). We confirm and add to recent evidence that digital rectal examination has a low predictive value and that many significant cancers at this PSA range may be missed. MATERIALS AND METHODS: From 1994 to 1997 a total of 10,523 participants 54 to 74 years old were randomized to screening in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. Of the participants 9,211 (87.5%) had PSA less than 4.0 ng./ml., and underwent digital rectal examination and transrectal ultrasonography. Expected rates of prostate cancer detection were calculated using logistic regression analysis. Radical prostatectomy was performed in about half of the 478 men diagnosed with prostate cancer. Tumors were characterized by pT category, Gleason score and cancer volume in 166 processed radical prostatectomy specimens. In 50 of these cases PSA was 0 to 4.0 ng./ml. RESULTS: The positive predictive value of digital rectal examination and transrectal ultrasonography at PSA 0 to 4.0 ng./ml. was only 9.7%. Positive predictive value strongly depended on PSA. Sensitivity was calculated by using estimates of the prevalence of sextant biopsy detectable prostate cancers. Of 760 detectable cancers 478 (67%) were diagnosed irrespective of PSA in men screened with digital rectal examination, transrectal ultrasonography and PSA. Only 127 of 348 detectable prostate cancers (36.5%) were actually diagnosed in men with PSA 2 to 4 mg./ml. The importance of these missed cancers was evaluated with parameters of tumor aggressiveness within PSA ranges. CONCLUSIONS: Approximately half of the tumors missed with PSA 0 to 4 ng./ml. had aggressive characteristics (Gleason score 7 or greater, Gleason 4-5 components) and were organ confined. These tumors should be diagnosed and treated according to the present understanding of their natural history. More sensitive and selective screening strategies are needed. Presently a wrong "window of opportunity" is used for early detection of prostate cancer.     

An artificial neural network for prostate cancer staging when serum prostate specific antigen is 10 ng./ml. or less

PURPOSE: An artificial neural network was developed to improve the prediction of pathological stage before radical prostatectomy based on variables available at biopsy and clinical parameters. MATERIALS AND METHODS: We used the prospectively accrued European prostate cancer detection data base to train an artificial neural network to predict pathological stage in 200 men with serum prostate specific antigen (PSA) 10 ng./ml. or less who underwent radical prostatectomy. Variables included in the artificial neural network were patient age, serum PSA, free-to-total PSA ratio, PSA velocity, transrectal ultrasound calculated total and transition zone volumes with their associated PSA parameters (transition zone PSA density and PSA density), digital rectal examination and Gleason score on biopsy. Two multilayer perceptron neural networks were trained on the remaining variables. Data on the 200 patients were divided randomly into a training set, a test set and a validation or prospective set. RESULTS: Overall classification accuracy of the artificial neural network was 92.7% and 84.2% for organ confined and advanced prostate cancer staging, respectively. For preoperatively predicting local versus advanced stage the area under the ROC curve for the artificial neural network was significantly larger (0.91) compared with logistic regression analysis (0.83), Gleason score (0.69), PSA density (0.68), prostate transition zone volume (0.63) and serum PSA (0.62) (all p <0.01). CONCLUSIONS: The artificial neural network outperformed logistic regression analysis and correctly predicted pathological stage in more than 90% of the validation patients with serum PSA 10 ng./ml. or less based on clinical, biochemical and biopsy data. In the future artificial neural networks may represent a significant step for improved staging of prostate cancer when counseling patients referred for radical prostatectomy or other curative treatments.