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.     

Comparison of contrast enhanced color Doppler targeted biopsy to conventional systematic biopsy: impact on Gleason score

PURPOSE: Prostate cancer grading with Gleason score is an important prognostic factor. This prospective randomized study compares ultrasound systematic biopsy vs contrast enhanced color Doppler targeted biopsy for the impact on Gleason score findings. MATERIALS AND METHODS: We examined 690 men (mean age 56 years, range 41 to 77) with a serum total prostate specific antigen of 1.25 ng/ml or greater, a free-to-total prostate specific antigen ratio less than 18% and/or a suspicious digital rectal examination. Contrast enhanced color Doppler targeted biopsies with a limited number of cores (5 or less) were performed in hypervascular areas of the peripheral zone during administration of the ultrasound contrast agent Sonovuetrade mark (Bracco, Milano, Italy). Ten systematic biopsies were obtained in a standard spatial distribution. Cancer detection rates and Gleason score were compared. RESULTS: Prostate cancer was identified in 221 of 690 subjects (32%) with a mean prostate specific antigen of 4.6 ng/ml (range 1.4 to 35.0). Prostate cancer was detected in 180 of 690 subjects (26%) with contrast enhanced color Doppler targeted biopsy and in 166 of 690 patients (24%) with systematic ultrasound biopsy. The Gleason score of all 180 cancers detected on contrast enhanced color Doppler targeted biopsy was 6 or higher (mean 6.8). The Gleason score of all 166 cancers detected on systematic biopsy ranged from 4 to 6 and mean Gleason score was 5.4. Contrast enhanced color Doppler targeted biopsy detected significantly higher Gleason scores compared to systematic biopsy (Wilcoxon rank sum test p <0.003). CONCLUSIONS: Contrast enhanced color Doppler targeted biopsy detected cancers with higher Gleason scores and more cancer than systematic biopsy. Therefore, contrast enhanced color Doppler seems to be helpful in the grading of prostate cancer, which is important for defining prognosis and deciding treatment.     

Percent free prostate specific antigen in the total prostate specific antigen 2 to 4 ng./ml. range does not substantially increase the number of biopsies needed to detect clinically significant prostate cancer compared to the 4 to 10 ng./ml. range

PURPOSE: Percent free prostate specific antigen (PSA) is useful to select patients for prostate biopsy with total PSA 4 to 10 ng./ml. However, 20% of men with PSA between 2.6 and 4 ng./ml. harbor significant prostate cancer and percent free PSA has been suggested to aid in the decision to biopsy in this total PSA range as well. Concerns exist that the number of biopsies needed to detect 1 cancer in this range may be inappropriately high. In a prospective referral population we evaluated sensitivity and specificity of various percent free PSA cutoffs and determined the biopsy-per-cancer ratio in the PSA 2 to 4 ng./ml. range in men with a benign digital rectal examination, and report on the biological nature of the detected cancers based on Gleason score. Results were compared to those obtained from a reference group of patients (PSA 4 to 10 ng./ml., benign digital rectal examination) from the same prospective referral cohort. MATERIALS AND METHODS: Total PSA and free PSA were measured and percent free PSA was calculated. Of the initial 1,602 men 756 had a benign digital rectal examination and PSA 4 to 10 ng./ml., and 219 had a benign digital rectal examination and PSA 2 to 4 ng./ml. Sensitivity, specificity, the number of true positive (evidence of cancer) and false-positive (no evidence of cancer) biopsies were determined. The ratio of true positive biopsies-to-all biopsies performed was used to determine the biopsy-per-cancer ratio. Gleason score of the detected cancers was evaluated. The procedure was repeated for the PSA 4 to 10 ng./ml. range. RESULTS: In the PSA 4 to 10 ng./ml. range a sensitivity of 63.7% to 92.5% with a specificity of 57.5% to 18.7% was found when percent free PSA was 18% to 25%. On average 3 biopsies were needed to detect 1 cancer. When PSA was 2 to 4 ng./ml. sensitivity was 46.3% to 75.6% and specificity was 73.6% to 37.6% when the same percent free PSA cutoff was examined. Calculation of the biopsy-per-cancer ratio for various percent free PSA cutoffs revealed that 3 to 5 biopsies were needed to find 1 cancer. Of 41 cancers detected in the PSA 2 to 4 ng./ml. range 6 had a Gleason score 5. The majority (28 of 41) of cases had a Gleason score of 6. Gleason score was 7 in 5 patients and 8 in 1. CONCLUSIONS: In the PSA 4 to 10 ng./ml. range high sensitivity for prostate cancer detection is critical and 3 biopsies are needed to detect 1 cancer. In the PSA 2 to 4 ng./ml. range a percent free PSA cutoff of 18% to 20% detected about 50% of cancers while sparing up to 73% of unnecessary biopsies with a biopsy-to-cancer ratio of 3 to 4:1. Percent free PSA can be applied to the PSA 2 to 4 ng./ml. range to detect prostate cancer and only moderately increases the number of biopsies needed to detect 1 significant cancer compared to the greater than 4 to 10 ng./ml. range.     

Prostate cancers scored as Gleason 6 on prostate biopsy are frequently Gleason 7 tumors at radical prostatectomy: implication on outcome

PURPOSE: Differentiation between Gleason score 6 and 7 in prostate biopsy is important for treatment decision making. Nevertheless, under grading errors compared with the actual pathological grade at radical prostatectomy are common. We compared the characteristics and outcomes of tumors that were scored 6 on prostate biopsy but were 7 on subsequent radical prostatectomy pathological evaluation to those in tumors with a consistent rating of Gleason score 6 or 7 at biopsy and surgery. MATERIALS AND METHODS: We performed a retrospective database analysis from our referral center (1989 to 2004). We compared pre-prostatectomy characteristics, radical prostatectomy pathological features and the post-radical prostatectomy prostate specific antigen failure rate, defined as any 2 consecutive detectable prostate specific antigen measurements, in 3 subgroups of patients, including 156 with matched Gleason score 6 in the prostate biopsy and radical prostatectomy, 205 with upgraded Gleason score 6/7, that is prostate biopsy Gleason score 6 and radical prostatectomy Gleason score 7, and 412 with matched Gleason score 7 in the prostate biopsy and radical prostatectomy. RESULTS: Radical prostatectomy Gleason score matched the prostate biopsy score in 38.2% of biopsy Gleason score 6 and 81.4% of biopsy Gleason score 7 cases. Higher prostate specific antigen was associated and an increased percent of cancer in the prostate biopsy was predictive of discordance between the prostate biopsy and radical prostatectomy Gleason scores (p <0.001). Margin (p = 0.0075) or seminal vesicle involvement (p = 0.0002), cancer volume (p <0.001) and the prostate specific antigen failures rate (p = 0.014) were significantly higher in under graded Gleason score 7 cancer compared to those in matched Gleason score 6 cases. However, they were comparable to those with a matched Gleason score 7 tumor grade (p = 0.66). CONCLUSIONS: Almost half of tumors graded Gleason score 6 at biopsy are Gleason score 7 at surgery. Upgraded Gleason score 6 to 7 tumors have outcomes similar to those of genuine Gleason score 7 cancer. For prostate biopsy Gleason score 6 tumors clinicians should consider the overall likelihood of tumor upgrading as well as specific patient characteristics, such as prostate specific antigen and the percent of tumor in the prostate biopsy, when contemplating treatments that are optimized for low grade tumors, including watchful waiting or brachytherapy.     

Prostate cancer risk assessment program: a 10-year update of cancer detection

PURPOSE: Guidelines for screening men at high risk for prostate cancer remain under investigation. We report our 10-year cancer detection data from the Prostate Cancer Risk Assessment Program, a longitudinal screening program for men at high risk. MATERIALS AND METHODS: Men between ages 35 and 69 years with a family history of prostate cancer, any black man regardless of family history or any patient with a known mutation in the BRCA 1 gene are eligible for the Prostate Cancer Risk Assessment Program and undergo longitudinal followup. Cancer detection, prostate cancer features and the predictive value of screening parameters were determined based on Prostate Cancer Risk Assessment Program biopsy criteria. RESULTS: A total of 609 men were accrued to the Prostate Cancer Risk Assessment Program as of the end of June 2006, of whom 61.2% were black. Of all participants 19% underwent prostate biopsies. The prostate cancer incidence was 9.0%, more than 90% of prostate cancers were Gleason score 6 or higher and 22% were Gleason score 7 or higher. The majority were organ confined. Of men diagnosed with prostate cancer 20% had a prostate specific antigen of less than 2.5 ng/ml and a free prostate specific antigen of less than 25% with a normal digital rectal examination. CONCLUSIONS: Our results support aggressive screening measures for men at high risk for prostate cancer. The majority of cancers detected were at a prostate specific antigen of less than 4.0 ng/ml with a fifth diagnosed at a prostate specific antigen of below 2.5 ng/ml. These cancers were intermediate to high grade and organ confined, indicating a greater likelihood of cure following local therapy in these men.     

The impact of pretreatment PSA on risk stratification in men with Gleason 6 prostate cancer: Implications for active surveillance

BackgroundThere are limited data to support the safety of active surveillance in men with favorable-intermediate risk prostate cancer due only to a prostate specific antigen (PSA) above 10 ng/ml. We therefore evaluated the impact of pretreatment PSA on risk-stratification in men with Gleason 6 prostate cancer.MethodsWe identified men aged 18 to 75 with cT1-2cN0cM0, pre-treatment PSA < 20 ng/ml, Gleason 6 prostate cancer diagnosed from 2010 to 2016 in the National Cancer Database who underwent radical prostatectomy. The associations of patient and disease features with Gleason score upgrading or adverse pathologic features at prostatectomy were evaluated using logistic regression. To evaluate for non linear relationships between PSA and each outcome, we examined predicted marginal event rates standardized for baseline characteristics with PSA modeled using restricted cubic splinesResultsA total of 75,566 patients were included in the cohort. In unadjusted analyses, patients with pretreatment PSA ≥ 10 ng/ml had higher rates of Gleason core upgrading (58.8% vs. 47.9%; P< 0.001) and adverse pathologic features (19.7% vs. 10.0%; P< 0.001) compared to patients with PSA < 10 ng/ml. In multivariable analyses, PSA ≥ 10 ng/ml was associated with statistically significantly increased risks of Gleason score upgrading (OR 1.47;95%CI 1.39 – 1.55) and adverse pathologic features (OR 2.15;95%CI 2.01 – 2.30). When modeled as a non linear continuous covariate, PSA was associated with increased adjusted rates of Gleason score upgrading and adverse pathologic features without a clear dichotomization at a threshold of 10 ng/ml.ConclusionHigher pretreatment PSA was independently associated with increased risks of Gleason score upgrading and adverse pathologic features at prostatectomy. Flexible modeling of the relationship between PSA and each outcome did not support dichotomization at a threshold of 10 ng/ml. These results can be used to improve patient risk-stratification for active surveillance.     

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.     

Under diagnosis and over diagnosis of prostate cancer in a screening population with serum PSA 2 to 10 ng/ml

PURPOSE: Since the implementation of widespread serum total prostate specific antigen based screening, the risk of prostate cancer over diagnosis has become a concern. We evaluated the amount of possible over and under diagnosis of prostate cancer in an asymptomatic screening population with a total prostate specific antigen of 2.0 to 3.9 (lower range) and 4.0 to 10.0 ng/ml (higher range). MATERIALS AND METHODS: A total of 680 patients with prostate cancer were included. Possible over diagnosis was defined as Gleason score less than 7, pathological stage pT2a and negative surgical margins. Under diagnosis was defined as pathological stage pT3 or greater, or positive surgical margins. Furthermore, insignificant tumors according to the Epstein criteria were evaluated in a small subset of patients for whom cancer volume information was available. RESULTS: In the lower and higher total prostate specific antigen ranges there was an over diagnosis rate of 19.7% and 16.5%, and an under diagnosis rate of 18.9%* and 36.7%, respectively (p<0.05). In the prostate specific antigen range of 2.0 to 10.0 ng/ml combined the rates of over and under diagnosis were 17.6% and 30.3%, respectively. In addition, 8.7% of tumors with total prostate specific antigen 2.0 to 10.0 ng/ml met the Epstein criteria for insignificance. CONCLUSIONS: These data show that the reported estimates of over diagnosis in the low total prostate specific antigen group are exaggerated in a screening population. Using our criteria prostate cancer under diagnosis occurs more frequently than over diagnosis in the total prostate specific antigen range of 4.0 to 10 ng/ml.     

Prediction of extraprostatic extension in the neurovascular bundle based on prostate needle biopsy pathology, serum prostate specific antigen and digital rectal examination

PURPOSE: There are few studies on predictors of extraprostatic extension (EPE) in the region of the neurovascular bundle (NVB). We investigated whether clinical information and prostate biopsy data could predict EPE of clinical localized prostate cancer. MATERIALS AND METHODS: Through a retrospective analysis of the pathology database we identified 2,660 cases of clinically localized prostate cancer treated with radical retropubic prostatectomy without preoperative adjuvant therapy at The Johns Hopkins Hospital. The study sample involved a total of 3,006 lobes with prostate cancer including 2,070 with organ confined disease, 620 with EPE in the NVB at the posterolateral edge of the prostate and 316 with EPE in a region other than the NVB (EPE elsewhere). Through univariate and multivariate logistic regression analysis we determined whether patient age, year of surgery, serum prostate specific antigen, digital rectal examination, biopsy highest Gleason score, perineural invasion, percent of side specific biopsy cores with cancer, percent of each core involved with cancer and the maximum percent of a core involved with cancer was predictive of EPE in the NVB. RESULTS: Prostate specific antigen (10 or greater vs less than 10), biopsy Gleason score (7 or greater vs 6 or less), digital rectal examination (abnormal vs normal), percent of side specific cores with tumor (greater than 33.3% vs 33.3% or less) and average percent involvement of each positive core (greater than 20% vs 20% or less) were all found to be statistically significant independent predictors of NVB penetration in multivariate analysis. The generated model stratifies each of these variables into high and low risk. The probability of EPE in the NVB was less than 10% in cases with 1 or fewer of the higher risk variables and was 10% or greater in cases with more than 1 of the higher risk variables. CONCLUSIONS: The model generated in this study allows for the preoperative identification of patients with 10% or greater probability of EPE in the NVB. Our algorithm will help provide objective parameters that aid in the decision to spare the NVB safely.     

High-grade prostate cancer is associated with low serum testosterone levels

BACKGROUND: The aim of this study was to assess whether low serum testosterone levels in men with newly diagnosed prostate cancer have an association to the endocrine status, prostate-specific antigen (PSA) levels, Gleason score, and androgen receptor expression. METHODS: Besides a full clinical work-up, the following hormones were quantified in men with newly diagnosed prostate cancer by serum analysis: total testosterone, human luteinising hormone (hLH), human follicle stimulating hormone (hFSH), estradiol, and dehydroepiandrostendione (DHEA). In a subgroup of men, androgen receptor expression was determined immunohistochemically. RESULTS: One hundred and fifty six patients (65.7 +/- 8.5 yrs) with a mean PSA of 29.8 ng/ml (median: 7.4 ng/ml) were analysed. Fifty-two patients (33%) had a partial androgen deficiency (serum testosterone < 3.0 ng/ml). These men had lower hLH (3.3 vs. 5.9 mIU/ml), hFSH (6.2 vs. 8.4 mIU/ml), and estradiol (18.8 vs. 29.1 pg/ml) serum levels. Mean Gleason score was higher (7.4 vs. 6.2) in men with a low serum testosterone, PSA-levels were lower (25.3 vs. 31.9 ng/ml). Mean testosterone levels decreased from 4.1 +/- 1.7 ng/ml in patients with Gleason scores < or = 5 to 2.8 +/- 2.7 ng/ml with Gleason scores > or = 8. Androgen receptor expression was higher in patients with low serum testosterone. CONCLUSIONS: Patients with high Gleason score prostate cancer have lower testosterone and estradiol serum levels. The fact that gonadotropins were lower in parallel suggests a tumor-mediated suppression of the hypothalamic-pituitary-gonadal hormone axis particularly in men with high Gleason score tumours.     

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.     

Perineural invasion and MIB-1 positivity in addition to Gleason score are significant preoperative predictors of progression after radical retropubic prostatectomy for prostate cancer

We assessed the use of clinical stage, serum prostate specific antigen, DNA ploidy, proliferation, and traditional histologic findings from the biopsy to predict prostate cancer progression after radical retropubic prostatectomy. Between 1995 and 1998, 454 consecutive patients with cancer on biopsy were treated by radical retropubic prostatectomy. Preoperative serum prostate specific antigen, clinical stage, Gleason score, percentage of cores and surface area positive for cancer, perineural invasion, and DNA ploidy and MIB-1 immunostain quantitation by image analysis were evaluated in a multivariate Cox proportional hazards regression model to predict cancer progression. Cancer progression was defined as a postoperative serum prostate specific antigen level of > or = 0.4 ng/mL, local recurrence, or systemic progression. Mean follow-up was 3.4 years (range 17 days to 5.8 years). Cancer progression was observed in 73 patients with a mean time to progression of 2.1 years (range 33 days to 5.1 years). Gleason score (p <0.001), MIB-1 cancer proliferation (p = 0.008), and perineural invasion (p = 0.008) were significantly associated with progression. Patients with cancer Gleason scores of 7 and >7 had a 2.5-fold and nearly 4-fold increased risk, respectively, of cancer progression compared with patients with cancer Gleason scores of < or = 6. Patients with perineural invasion at biopsy were twice as likely to progress compared with patients without perineural invasion. Each 1-unit increase in MIB-1 on the natural logarithmic scale increased the risk of cancer progression by 64%. Cancer progression models that include serum prostate specific antigen and clinical stage may require revision to incorporate perineural invasion and MIB-1 proliferative activity in addition to Gleason score.     

Changing nature of high risk patients undergoing radical prostatectomy

PURPOSE: We examined the outcomes of radical prostatectomy alone in high risk patients with prostate cancer and evaluated changes in high risk prostate cancer outcomes with time. MATERIALS AND METHODS: From 1988 to 2003, 251 men with high risk prostate cancer (prostate specific antigen more than 20 ng/ml and/or biopsy Gleason greater than 7) were identified in a cohort of 1,796 (14%) enrolled in the Shared Equal Access Regional Cancer Hospital Database. Temporal changes in clinicopathological characteristics and prostate specific antigen recurrence rates were examined stratified by 4, 4-year periods. RESULTS: With time significantly more men were considered at high risk due to a high biopsy Gleason score relative to prior years, when the most common reason for being considered at high risk was increased PSA (p <0.001). Only 3% of high risk men from 2000 to 2003 had increased prostate specific antigen and high biopsy Gleason score compared to 23% from 1988 to 1991. With time there were no differences in biochemical recurrence rates (p = 0.147). Men with a high biopsy Gleason score and increased prostate specific antigen had worse outcomes than men with only a high Gleason score or men with only high prostate specific antigen (p = 0.046 and 0.081, respectively). On multivariate analysis that only included preoperative clinical characteristics only prostate specific antigen was an independent predictor of prostate specific antigen failure following radical prostatectomy (p = 0.014). There was a trend, which did not attain statistical significance, for higher biopsy Gleason scores and higher clinical stage to be associated with higher failure rates (p = 0.060 and 0.081, respectively). CONCLUSIONS: Patients are designated as high risk by Gleason grade more commonly now than early in the prostate specific antigen era. Outcomes in high risk patients undergoing radical prostatectomy alone have not significantly improved with time. New treatment strategies, such as multimodality therapy, are needed to improve outcomes in high risk patients with prostate cancer.     

Associations of serum testosterone with microvessel density,androgen receptor density and androgen receptor gene polymorphism in prostate cancer

PURPOSE: We investigate potential associations of serum testosterone with microvessel density, androgen receptor expression and AR gene polymorphism in men with untreated prostate cancer. MATERIAL AND METHODS: Serum luteinizing hormone, follicle-stimulating hormone, estradiol and testosterone were determined in men with newly diagnosed prostate cancer. The number of tumor vessels per 0.46 mm. and androgen receptor density (as the percent positive nuclei) were quantified immunohistochemically on prostate cancer areas of prostate biopsy specimens. Polymorphisms within the AR gene (number of CAG repeats) were determined by polymerase chain reaction and restriction fragment length polymorphism analysis using DNA from peripheral blood. RESULTS: The 39 men entered into this study were grouped into 16 with low (3 ng./ml. or less, group 1) and 23 with normal (greater than 3 ng./ml., group 2) serum testosterone. Mean prostate specific antigen +/- SD was significantly lower in group 1 than in group 2 (18.8 +/- 11.1 versus 27.2 +/- 12.2 ng./ml., p = 0.03). Mean Gleason score (7.4 +/- 1.3 versus 6.0 +/- 1.2, p = 0.01), androgen receptor density (96.6% +/- 2.8% versus 84.8% +/- 7.2%, p = 0.03) and tumor vessel density (63.0 +/- 30.8/0.46 versus 39.0 +/- 22.9/0.46 mm.2, p = 0.007) were significantly higher in group 1 than in group 2. The number of CAG repeats within the AR gene did not correlation with serum androgen. CONCLUSIONS: Low serum testosterone in men with newly diagnosed prostate cancer is associated with higher tumor microvessel and androgen receptor density as well as with higher Gleason score, suggesting enhanced malignant potential.     

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.     

Effect of prostate volume on tumor grade in patients undergoing radical prostatectomy in the era of extended prostatic biopsies

PURPOSE: We investigated the influence of prostate volume on biopsy and prostatectomy Gleason score, the incidence of upgrading and total tumor volume. MATERIALS AND METHODS: From 1997 to 2004, 247 patients were diagnosed with prostate cancer by multisite extended prostatic biopsy (10 or 11 cores) and underwent radical prostatectomy at our institution without neoadjuvant therapy. Medical records were reviewed to determine patient age at diagnosis, preoperative prostate specific antigen, prostate volume, clinical stage, biopsy Gleason score, pathological stage, prostatectomy Gleason score and total tumor volume. The Mann-Whitney and chi-square tests were used to compare variables among groups and multivariate regression analysis was used to determine predictors of Gleason score. RESULTS: Median patient age was 61 years and median preoperative prostate specific antigen was 5.5 ng/ml. Median prostate volume on transrectal ultrasound was 37 cc. Prostatectomy Gleason score was 6 in 31% of cases, 7 in 57% and 8-9 in 12%. Prostate volume greater than 50 cc was significantly associated with a higher incidence of well differentiated tumors (Gleason score 6) at prostatectomy, that is 17.9% in patients with a prostate volume of 25 cc or less, 28.9% in those with a prostate volume of 25 to 50 cc and 45.3% in those with a prostate volume of greater than 50 cc (p<0.01). In addition, the incidence of tumor upgrading was significantly lower in patients with a large prostate volume (greater than 50 cc) compared to that in those with a smaller prostate volume (20.8% vs 36.1%, p<0.05), particularly in the subset with biopsy Gleason score 6 (24% vs 54.1%, p<0.01). Patients with a large prostate volume (greater than 50 cc) had smaller total tumor volume with a trend toward statistical significance (median total tumor volume 0.86 vs 1.1 cc, p=0.0631). CONCLUSIONS: In the era of extended prostatic biopsies patients with a large prostate volume have a significantly higher incidence of well differentiated tumor at prostatectomy and a lower likelihood of tumor upgrading.     

The Predictors of Pelvic Lymph Node Metastasis at Radical Retropubic Prostatectomy

PurposeWe studied preoperative variables in a contemporary series of patients who underwent radical retropubic prostatectomy (RRP) to determine which variables were associated with lymph node metastasis.Materials and MethodsBetween January 1995 and November 1999, 1,091 men underwent RRP, 695 of whom underwent bilateral pelvic lymph node dissection without any prior therapy. We evaluated biopsy Gleason score, maximum tumor length and maximum percentage of tumor in the positive core(s), location and number of positive cores, and total prostate specific antigen before surgery in 295 of these patients. We also developed a classification and regression tree analysis algorithm to segregate the risk of positive lymph node metastasis. Stepwise logistic regression analyses were used to determine independent predictors of lymph node metastasis.ResultsOf the 695 patients 19 (2.7%) had lymph node metastasis. Clinical stage, Gleason score, positive basal core, greatest percentage of tumor on positive cores and maximum tumor length in positive core were significant predictors of lymph node metastasis in the Mann-Whitney U test and chi-square test. Classification and regression trees analysis revealed that 4 or more positive cores with any Gleason grade 4 or 5, serum prostate specific antigen 15.0 ng/ml or greater, or the presence of dominant Gleason 4 or 5 were independent predictors of lymph node metastasis. Our algorithm had a significantly higher diagnostic performance than the Hamburg algorithm (p = 0.002).ConclusionsOur algorithm may be a valid tool for the prediction of lymph node metastasis and may help to select men who do not need to undergo bilateral pelvic lymph node dissection with RRP.     

Contemporary preoperative parameters predict cancer-free survival after radical prostatectomy: a tool to facilitate treatment decisions

Prostate specific antigen (PSA) screening has heralded stage migration in prostate cancer toward cancers that may be readily eliminated by primary intervention. We sought to identify contemporary, preprostatectomy measures of cancer severity useful and significant for predicting postprostatectomy, recurrence-free survival. The association of baseline variables clinical variables (age, clinical stage, serum PSA, and race) and prostate biopsy parameters (Gleason score, presence of perineural invasion, number of biopsy cores with cancer, and the greatest percentage of a biopsy core occupied by cancer--GPC) with recurrence-free survival was evaluated by multivariate Cox proportional hazards regression among consecutive patients that underwent radical prostatectomy as primary therapy between 1994 and 2002. Tables were generated depicting expected 5-year recurrence-free survival after prostatectomy. From 1414 patients, 183 developed biochemical recurrence, 8 died from prostate cancer, and 31 died of all causes. Multivariable Cox regression found that clinical stage, PSA, Gleason score, and the greatest percentage of a biopsy core involved by cancer (GPC), were each significant determinants of post-prostatectomy, PSA recurrence-free survival (P < 0.05 for each). Gleason score and GPC were also significantly associated with clinical recurrence-free survival and cancer death, whereas other biopsy parameters and PSA were not. The amount of cancer in a biopsy core is a significant predictor of recurrence-free survival after prostatectomy, and is a simple clinical measure that complements baseline PSA, and Gleason score in predicting outcome. Tabulated 5-year PSA-free survival outcomes, stratified by these preoperative parameters, provide a basis for preoperative counseling of patients regarding postprostatectomy cancer control expectations.     

The relationship between tumor volume and the number of positive cores in men undergoing multisite extended biopsy: implication for expectant management

PURPOSE: We assessed the relationship between the number of positive cores obtained at extended biopsy and tumor volume in radical prostatectomy specimens as a tool for predicting the biological significance of prostate cancer from biopsy data. MATERIALS AND METHODS: The study group included 207 men who were treated with radical prostatectomy without neoadjuvant therapy at our cancer center. All patients were diagnosed by systematic extended biopsy (10 or 11 cores) performed between 1997 and 2003. The variables analyzed were patient age, prostate specific antigen, clinical stage, biopsy Gleason score, maximum tumor length in a core, greatest percent of tumor in a core, total tumor length, total percent of tumor in all cores, positive core location, initial or repeat biopsy and prostate volume in subgroups based on the number of positive cores, that is group 1-1, group 2-2 and group 3-3 or more cores. Bivariate correlation analysis and multiple logistic regression analysis were used to determine the predictors of insignificant cancer. RESULTS: The number of positive cores was significantly related to total tumor volume (r = 0.433, p <0.001). Insignificant prostate cancer (volume less than 0.5 cc and Gleason score 6 or less) was found in 21.7% of patients (45 of 207). The incidence of insignificant cancer was 42.5% (31 of 73 patients) in group 1, 16.4% (10 of 61) in group 2 and 5.5% (4 of 73) in group 3. There was a significant difference in the incidence of insignificant cancer among the subgroups (group 1 vs 2 p <0.001, group 1 vs 3 p <0.0001 and group 2 vs 3 p <0.05). The best model for predicting insignificant cancer in group 1 was the combination of tumor length less than 2 mm, Gleason score 3 + 4 or less and prostate volume greater than 50 cc with 83.9% sensitivity (26 of 31 patients) and 61.9% specificity (26 of 42). CONCLUSIONS: The probability of insignificant cancer was directly related to the number of positive cores. Tumor length in a core, Gleason score and prostate volume significantly enhanced the prediction model for insignificant cancer in men with 1 positive core who underwent extended biopsy.     

High dose rate brachytherapy as a boost for the treatment of localized prostate cancer

PURPOSE: We report the outcome and toxicities of high dose rate brachytherapy as a boost for localized prostate cancer. MATERIALS AND METHODS: Between 1996 and 2003, 309 patients with prostate carcinoma were treated with external beam radiation therapy and high dose rate brachytherapy. Furthermore, 36% of the patients received neoadjuvant/concurrent or adjuvant androgen deprivation therapy. Patients were stratified into 3 groups. Group 1 of 67 patients had Gleason score 6 or less, pretreatment prostate specific antigen 10 ng/ml or less and clinical stage T2a or less. Group 2 of 109 patients had Gleason score 7 or greater, pretreatment prostate specific antigen greater than 10 ng/ml and clinical stage T2b or greater. Group 3 of 133 patients had 2 or more of these higher risk factors. RESULTS: At a median followup of 59 months the 5-year biochemical control rate, as defined by the American Society for Therapeutic Radiation and Oncology, was 86%, cause specific survival was 98% and overall survival was 91%. Biochemical control in stratified groups 1 to 3 was 98%, 90% and 78%, respectively. On univariate analysis risk group, pretreatment prostate specific antigen and Gleason score were significant predictors of biochemical control. However, on multivariate analysis only risk group and pretreatment prostate specific antigen were significant. Using the Common Toxicity Criteria scale there were 2 cases of grade 3 acute urinary toxicity. Regarding late side effects 4% of patients had grade 3 genitourinary toxicity and 1 had a grade 4 rectal complication. CONCLUSIONS: External beam radiation therapy and high dose rate brachytherapy for prostate cancer resulted in excellent biochemical control, cause specific survival and overall survival with minimal severe acute or late complications.