External beam radiation therapy after radical prostatectomy: efficacy and impact on urinary continence.

INTRODUCTION AND OBJECTIVES: The efficacy of adjuvant and salvage external beam radiation (AXRT+SXRT) for prostate cancer after radical prostatectomy (RP) has been debated because of the inability to rule out systemic occult metastasis, uncertainty that radiation eradicates residual local disease and the potential of exacerbating impotency and incontinence. To characterize the effectiveness and treatment morbidity a retrospective review was performed. METHODS: In all, 38 patients received AXRT and 91 received SXRT. The SXRT group was stratified by PSA level, age, race, pathologic stage, margin status, worst Gleason sum, radiation dose and pelvic field. Complications evaluated were impotence and incontinence. Median follow-up was 60.2 months. RESULTS: The 5-y disease-free survival (DFS) rate was 61.3% for AXRT and 36.3% for SXRT. Multivariate analysis of the SXRT cohort showed Gleason score, pathologic stage and pre-XRT PSA to be predictors of disease recurrence. After XRT 26% had worsened continence. CONCLUSIONS: Patients who recur after RP whose pathologic stage is pT2 or pT3c, Gleason score of 8 or higher or pre-XRT PSA is >2.0 ng/dl may have microscopic metastatic disease and a decreased chance of cure with SXRT alone. Continence was further impaired after XRT.

Investigating the distribution of prostate cancer using three-dimensional computer simulation.

The objective of this work was to investigate the distribution of prostate cancer using three-dimensional (3-D) computer simulation. Two hundred and eighty-one 3-D computer prostate models were constructed from radical prostatectomy specimens. An algorithm was developed which divided each model into 24 symmetrical regions, and it then detected the presence of tumor within an individual region. The distribution rate of prostate cancer was assessed within each region of all 281 prostate models, and the difference between the rates was statistically analyzed using Mantel-Haenszel methodology. There was a statistically significant higher distribution rate of cancer in the posterior half (57.2%) compared to the anterior half ( 40.5%; P=0.001). The base regions (36.8%) had a statistically significant lower distribution rate than either the mid regions (56.3%; P=0.001) or the apical regions (53.5%; P=0.001). The mid regions did have a statistically significant higher distribution rate compared to the apical regions (P=0.032). There was no statistically significant difference between the distribution rate on the left half (48.5%) compared to that on the right half (49.2%; P=0.494). The spatial distribution of prostate cancer can be analyzed using 3-D computer prostate models. The results illustrate that prostate cancer is least commonly located in the anterior half and base regions of the prostate. Through an analysis of the spatial distribution of prostate cancer, we believe that new optimal biopsy strategies and techniques can be developed.

Primary hormonal therapy for prostate cancer: experience with 135 consecutive PSA-ERA patients from a tertiary care military medical center.

The use of prostate specific antigen (PSA) in the 1990s has brought on a stage migration of prostate cancer. Despite that, many men have still presented with metastatic prostate cancer in the past decade. The use of primary hormone therapy in the PSA era at a tertiary care Army Medical Center is studied in this paper. Charts were reviewed of 135 men who were diagnosed with metastatic prostate cancer and treated with hormone therapy as a primary treatment between 1989 and 1995. Statistical analysis was used to determine significant predictor variables on the time to disease progression. In univariate analysis clinical stage, pretreatment alkaline phosphatase and nadir PSA values were significant predictors of time to progression. Race and type of treatment were not. In multivariate analysis the relative risk of progression was 3.2 for patients with an alkaline phosphatase >252 and 16.5 for patients with a nadir >2.0. This study supports the argument that racial disparities in prostate cancer outcomes are due to access to care. Furthermore, the survival rate for patients with D-2 disease is better than in the pre PSA studies. Clinical stage, pretreatment alkaline phosphatase and PSA nadir can be used to predict response for those men presenting with metastatic prostate cancer.

Improvements in pathologic staging for African-American men undergoing radical retropubic prostatectomy during the prostate specific antigen era: implications for screening a high-risk group for prostate carcinoma.

BACKGROUND: The objective was to compare the changes in pathologic and clinical data over time for African-American (AA) and white men with prostate carcinoma undergoing radical prostatectomy in an attempt to determine the early impact of prostate specific antigen (PSA). METHODS: Data from 195 AA and 587 white men who underwent radical prostatectomy from 1988 to 1999 in an equal access, tertiary, military medical facility were collected. Statistical analysis was used to determine the significance of the changes in the rates of extracapsular extension (ECE), positive margins, pretreatment PSA levels, and age at the time of surgery for each race over time. RESULTS: Comparing 1988-99 results, the authors found that the percentage of AA men with ECE decreased from 100% to 34.8% (P = 0.007), and for white men from 56.9% to 43.2% (P = 0.269). The percentage of AA men with positive margins decreased from 100% to 26.1% (P < 0.0001), and for white men from 41.2% to 27.0% (P = 0.021). Mean age at surgery decreased from 66.6 to 59.9 years for AA men (P < 0.001) and from 65.9 to 61.1 years for white men (P < 0.001). Also, PSA levels decreased from 10.1 to 6.6 ng/dL for white men (P < 0.001) and from 16.5 to 6.5 ng/dL for AA men (P < 0.001). CONCLUSIONS: The authors believe that the decrease in ECE and positive margins in AA men is primarily because of PSA testing, coupled with improved public awareness and equal access to care. It appears reasonable to recommend PSA testing in AA men, who have historically experienced poor outcomes from prostate carcinoma.

Use of serum creatinine to predict pathologic stage and recurrence among radical prostatectomy patients.

OBJECTIVES: To assess serum creatinine as a putative marker for staging/prognosis in localized prostate cancer. Although clinical stage, tumor grade, serum prostate-specific antigen (PSA), and tumor volume assessment by biopsy positivity are established prognostic markers in prostate cancer, the need for additional serum markers is clear. In a prior neural network analysis by our group, serum creatinine appeared to improve staging and prognosis. Even though serum creatinine is one of the most common blood tests used by practicing urologists, it has not been tested rigorously as a potential staging/prognosis marker in localized prostate cancer. METHODS: The data on 409 patients who underwent radical prostatectomy at the Walter Reed Army Medical Center between 1990 and 1996 were analyzed. Logistic regression analysis was used to evaluate the ability of serum creatinine to predict the pathologic stage. The ability of creatinine to predict PSA recurrence was also assessed using Cox regression analysis. In multivariable analyses, creatinine was assessed while simultaneously controlling for race, age, prostate weight, clinical stage, Gleason (World Health Organization) grade, prostatism history, treatment of benign prostatic hyperplasia, and pretreatment PSA level. RESULTS: Creatinine ranged from 0.1 to 2.3 mg/dL (mean and median 1.1 mg/dL). The relationship of creatinine to pathologic stage was significant (P = 0.050). As the level of creatinine increased, the proportion of patients with extraprostatic disease generally decreased. In multivariable logistic regression analysis, creatinine was not a significant predictor (P = 0.270). The relationship of the creatinine level to PSA recurrence was not significant in the univariate or multivariable analysis. CONCLUSIONS: Creatinine did not provide independent information for predicting pathologic stage or disease recurrence in patients with early prostate cancer.

Predicting risk of prostate specific antigen recurrence after radical prostatectomy with the Center for Prostate Disease Research and Cancer of the Prostate Strategic Urologic Research Endeavor databases.

PURPOSE: Biostatistical models to predict stage or outcome in patients with clinically localized prostate cancer with pretreatment prostate specific antigen (PSA), Gleason sum on biopsy or prostatectomy specimen, clinical or pathological stage and other variables, including ethnicity, have been developed. However, to date models have relied on small subsets from academic centers or military populations that may not be representative. Our study validates and updates a model published previously with the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE, UCSF, Urology Outcomes Research Group and TAP Pharmaceutical Products, Inc.), a large multicenter, community based prostate cancer database and Center for Prostate Disease Research (CPDR), a large military database. MATERIALS AND METHODS: We validated a biostatistical model that includes pretreatment PSA, highest Gleason sum on prostatectomy specimen, prostatectomy organ confinement status and ethnicity, including white and black patients. We then revised it with the Cox regression analysis of the combined 503 PSA era surgical cases from the CPDR prospective cancer database and 1,012 from the CaPSURE prostate cancer outcomes database. RESULTS: The original equation with 3 risk groups stratified CaPSURE cases into distinct categories with 7-year disease-free survival rates of 72%, 42.1% and 27.6% for low, intermediate and high risk men, respectively. Parameter estimates obtained from a Cox regression analysis provided a revised model equation that calculated the relative risk of recurrence as: exponent (exp)[(0.54 x Race) + (0.05 x sigmoidal transformation of PSA [PSA(ST)]) + (0.23 x Postop Gleason) + (0.69 x Pathologic stage). The relative risk of recurrence, as calculated by the aforementioned equation, was used to stratify the cases into 4 risk groups. Very low-4.7 or less, low-4.7 to 7.1, high-7.1 to 16.7 and very high-greater than 16.7, and patients at risk had 7-year disease-free survival rates of 85.4%, 66.0%, 50.6% and 21.3%, respectively. CONCLUSIONS: With a broad cohort of community based, academic and military cases, we developed an equation that stratifies men into 4 discrete risk groups of recurrence after radical prostatectomy and confirmed use of a prior 3 risk group model. Although the variables of ethnicity, pretreatment PSA, highest Gleason sum on prostatectomy specimen and organ confinement status on surgical pathology upon which the model is based are easily obtained, more refined modeling with additional variables are needed to improve prediction of intermediate risk in individuals.

Prostate cancer in men age 50 years or younger: a review of the Department of Defense Center for Prostate Disease Research multicenter prostate cancer database.

PURPOSE: Prostate cancer in men age 50 years or younger traditionally has accounted for approximately 1% of those diagnosed with prostate cancer. Prior studies of prostate cancer in men of this age led many clinicians to believe that they have a less favorable outcome than older men. Most of these studies were conducted before the advent of prostate specific antigen (PSA) screening programs. We evaluated a surgically treated cohort of men age 50 years or younger to determine whether disease recurred more frequently among them than in those 51 to 69 years old in the PSA era. MATERIALS AND METHODS: We reviewed the medical records of 477 men who underwent radical prostatectomy between 1988 and 1997. Age, ethnicity, preoperative PSA, clinical and pathological stage, margin and seminal vesicle involvement, and recurrence were compared between 79 men age 50 years or younger (study group) and 398, 51 to 69 years old (comparison group). Disease-free survival rates were compared using Kaplan-Meier and Cox regression techniques. RESULTS: There were 6 (7.6%) recurrences in the study group (79) and 107 (26.9%) in the comparison group (398). The disease-free survival curves were significantly different (log-rank p = 0.010). Age remained a significant prognostic factor (Wald p = 0.033) in multivariate Cox regression analyses that controlled for race, clinical and pathological stage, and pretreatment PSA. Similar results were found when the comparison group was limited to 116 patients 51 to 59 years old (log-rank p = 0.034, Wald p = 0.069). CONCLUSIONS: These data suggest that patients in the PSA era who underwent radical prostatectomy and were age 50 years or younger have a more favorable disease-free outcome compared to older men.

3-D computer visualization and interactive prostate biopsy simulation leads to an improved systematic technique for the detection of prostate cancer: clinical correlation.

OBJECTIVES: Urologists routinely use the systematic sextant needle biopsy technique to detect prostate cancer. However, recent evidence suggests that this technique has a significant sampling error. Recent data based upon whole-mounted step-sectioned radical prostatectomy specimens using a 3-D computer assisted prostate biopsy simulator suggests that an increased detection rate is possible using laterally placed biopsies. A new 10-core biopsy pattern was shown to be superior to the traditional sextant biopsy. This pattern includes the traditional sextant biopsy cores and four laterally placed biopsies in the right and left apex and mid portion of the prostate gland. The objective of this study is to confirm the higher prostate cancer detection rate obtained using the 10-core biopsy pattern in a small cohort of patients. METHODS: We retrospectively reviewed 35 consecutive patients with a pathologic diagnosis of prostate cancer biopsied by a single urologist using the 10-core biopsy pattern. The frequency of positive biopsy was determined for each core. Additionally, the sextant and 10-core prostate biopsy patterns were compared with respect to prostate cancer detection rate. RESULTS: Of the 35 patients diagnosed with prostate cancer, 54.3% (19/35) were diagnosed when reviewing the sextant biopsy data only. Review of the 10-core pattern revealed that an additional 45.7% (16/35) of patients were diagnosed solely with the laterally placed biopsies. The laterally placed biopsies had the highest frequency of positive biopsies when compared to the sextant cores. CONCLUSIONS: Our results suggest that biopsy protocols that use laterally placed biopsies based upon a five region anatomical model are superior to the routinely used sextant prostate biopsy pattern. Lateral biopsies in the apex and mid portion of the gland are the most important.

Investigating 3D tumor distribution for optimized diagnosis of prostate cancer.

Transrectal Ultrasonography (TRUS) based systematic needle biopsy of the prostate has been widely used clinically in the diagnosis of prostate carcinoma. Current protocols for prostate biopsy, such as the Sextant Protocol, however, have been proven to be insufficient in cancer detection since these protocols were built without having accurate information on 3D distribution of prostate cancers. In this research, our goal is to optimize prostate biopsy protocols by statistically investigating spatial distributions of prostate cancers. Based on the low-resolution nature of ultrasound imaging and the current clinical conventions, we propose to divide each individual prostate gland into different zones that are can be recognized and accessed by the urologists with ultrasound images during biopsy. By calculating cancer appearance inside each of these zones using a large number of prostate samples, we get the overall distributions of prostate cancers based on which an optimal biopsy protocol can be developed.

Inflammatory infiltrate (prostatitis) in whole mounted radical prostatectomy specimens from black and white patients is not an etiology for racial difference in prostate specific antigen.

PURPOSE: Although black men with and without prostatic carcinoma in general have higher levels of prostate specific antigen (PSA) than other racial groups, the cause is unknown. Previous studies have shown that black men produce greater PSA per cc of benign gland volume. We determined whether prostatic inflammation varied by race and could account for the racial difference in PSA among prostate cancer patients. MATERIALS AND METHODS: Between April 1993 and February 1997, 238 patients underwent radical prostatectomy for clinically localized prostate cancer at Walter Reed Army Medical Center and whole mounted specimens were processed at the Armed Forces Institute of Pathology. Cases were reviewed by 2 pathologists (W. Z. and I. A. S.) blinded to clinical information, and scored for inflammation as 0--rare; 1--mild, 10 to 15 small foci; 2--moderate, greater than 15 foci with a large area or greater than 20 small foci; 3--marked, greater than 20 small foci with a large area, and 4--diffuse, multiple large areas. The extent of inflammation was correlated to pretreatment PSA and other variables. RESULTS: A total of 181 white and 57 black men were evaluated. Of the patients 28 were excluded from analysis due to prior hormonal therapy. The percentage of patients with inflammation scores from 1 to 4 was higher among white (113 of 161, 70.2%) than black (30 of 49, 61.2%) men but this difference was not significant (p = 0.299) and the extent of inflammation was not significantly related to racial variation in serum PSA. CONCLUSIONS: To our knowledge no significant racial difference exists in the extent of inflammatory infiltrate, and inflammation was not the etiology of the racial difference in serum PSA levels in this clinically localized prostate cancer cohort.

The role of pretreatment serum albumin to predict pathological stage and recurrence among radical prostatectomy cases.

Serum albumin level has been implicated as a prognostic factor in various cancers, however it has not been studied in early stage prostate cancer. We examine the clinical prognostic value of the readily available pretreatment albumin level as a marker for determining staging and prognosis for men undergoing radical prostatectomy. A retrospective review was performed on 354 patients who underwent a radical prostatectomy at a tertiary facility from 15 April, 1990 until 3 December, 1996 who had a pretreatment serum albumin within 6 months prior to surgery. Albumin levels were analyzed and compared to the values of standard prognostic factors to assess the ability of albumin to predict pathological stage and serological recurrence by PSA level after radical prostatectomy. Albumin level was not of value in predicting serological disease recurrence, but interestingly was an independent prognostic factor in predicting risk of nonorgan-confined disease (T3 or T4). Our data also showed that, as expected, grade and pretreatment PSA levels were independent predictors of pathological stage. Albumin appears to be of clinical utility to augment assessment of pretreatment pathological stage. However, it is not of value in predicting serological disease recurrence following radical prostatectomy. Further study in other cohorts and in using additional analysis such as neural networks is indicated. Prostate Cancer and Prostatic Diseases (2000) 3, 186-190

Lateral biopsies added to the traditional sextant prostate biopsy pattern increases the detection rate of prostate cancer.

Urologists routinely use the systematic sextant needle biopsy technique to detect prostate cancer. However, recent evidence suggests that this technique has a significant sampling error and data based upon whole-mounted step-sectioned radical prostatectomy specimens using a three-dimensional computer-assisted prostate biopsy simulator suggests that an increased detection rate is possible using laterally placed biopsies. The simulated 10-core biopsy pattern (traditional sextant biopsy cores and four laterally placed biopsies in the right and left apex and mid portion of the prostate gland) was shown to be superior to the traditional sextant biopsy. The objective of this pilot study was to confirm the higher prostate cancer detection rate obtained using the 10-core biopsy pattern in patients. We reviewed data on 35 consecutive patients with a pathologic diagnosis of prostate cancer biopsied by a single urologist using the 10-core biopsy pattern. The frequency of positive biopsy was determined for each core. Additionally, the sextant and 10-core prostate biopsy patterns were compared with respect to prostate cancer detection rate. Of the 35 patients diagnosed with prostate cancer, 54.3%(19/35) were diagnosed by the sextant biopsy only. The 10-core pattern resulted in an additional 45.7%(16/35) of patients being diagnosed solely with the laterally placed biopsies. The laterally placed biopsies had the highest frequency of positive biopsies when compared to the sextant cores. In conclusion, biopsy protocols that use laterally placed biopsies based upon a five region anatomical model are superior to the routinely used sextant prostate biopsy pattern. Prostate Cancer and Prostatic Diseases (2000) 3, 43-46

p53 and bcl-2 immunohistochemistry in pretreatment prostate needle biopsies to predict recurrence of prostate cancer after radical prostatectomy.

PURPOSE: Immunohistochemical staining of radical prostatectomy specimens for p53 and bcl-2 proteins has been shown to correlate with prostate specific antigen (PSA) recurrence in a series of patients at our institution. We analyzed the relationship between staining of diagnostic prostate needle biopsies for p53 and bcl-2, and PSA recurrence. MATERIALS AND METHODS: From 1986 to 1993, 335 radical prostatectomies were performed at our hospital. Of the prostatectomy specimens 199 had been evaluated for p53 and bcl-2 proteins in a prior series. Of 139 patients with biopsy material available for analysis 129 had enough for evaluation of 1 or both markers. Prospectively obtained clinical followup data were available, with a mean followup of 6 years. Commercially available antibodies were used for immunohistochemical staining. RESULTS: The overall PSA recurrence rate was 37.6% for 199 radical prostatectomy cases and 37.9% for 129 with biopsy immunohistochemical staining. Staining of prostatectomies correlated well with PSA recurrence for p53 (p = 0.004) and bcl-2 (p = 0.001). However, biopsy staining did not correlate with prostatectomy staining or PSA recurrence for either marker. CONCLUSIONS: The p53 and bcl-2 biomarkers appear to be important to predict recurrence of prostate cancer when prostatectomy specimens are analyzed but this usefulness is not apparent with immunohistochemical staining of prostate biopsies. This difference may reflect sampling error and/or the heterogeneous nature of prostate cancers, and deserves further study.

Racial differences in tumor volume and prostate specific antigen among radical prostatectomy patients.

PURPOSE: Black men with and without prostate cancer in general have higher prostate specific antigen (PSA) before screening and treatment than other racial groups. A preliminary study suggested that higher PSA levels may be primarily due to greater tumor burden. We compared PSA and 3-dimensional (D) tumor volume in a consecutive cohort of black and white radical prostatectomy patients in an equal access military health care setting to determine racial differences in these parameters. MATERIALS AND METHODS: Prospective data collection, 2.25 mm. step section whole mount specimen processing and 3-D tumor volume assessment were performed in 226 patients with clinical stage T1-T3 prostate cancer undergoing radical prostatectomy at our center between April 1993 and March 1997. Of the patients 25 were excluded from further analysis because of neoadjuvant hormone treatment, T3 disease or Asian race. A total of 155 white and 46 black patients were compared. RESULTS: There was no significant racial difference in the distribution of patients by age, clinical stage, pathological stage, Gleason sum or benign prostate gland volume. A significant racial difference was noted for pretreatment PSA and 3-D tumor volume. PSA values were higher in black men than in white men, and the racial difference remained statistically significant in multivariate analysis adjusting for 3-D tumor volume, benign gland volume, age, stage and Gleason sum. CONCLUSIONS: Racial difference in PSA persists, despite rigorous covariate adjustment, and further study is needed to explain this PSA difference.

Three-dimensional computer-simulated prostate models: lateral prostate biopsies increase the detection rate of prostate cancer.

OBJECTIVES: Urologists routinely use the systematic sextant needle biopsy technique to detect prostate cancer. However, recent evidence suggests that this technique has a significant sampling error. We developed a novel three-dimensional (3D) computer-assisted prostate biopsy simulator based on whole-mounted step-sectioned radical prostatectomy specimens to compare the diagnostic accuracy of various prostate needle biopsy protocols. METHODS: We obtained digital images of 201 step-sectioned whole-mounted radical prostatectomy specimens. 3D computer simulation software was developed to accurately depict the anatomy of the prostate and all individual tumor foci. Additional peripheral devices were incorporated into the system to perform interactive prostate biopsies. We obtained 18 biopsies of each prostate model to determine the detection rates of various biopsy protocols. RESULTS: The 10- and 12-pattern biopsy protocols had a 99.0% detection rate; the traditional sextant biopsy protocol rate was only 72.6%. The 5-region biopsy protocol had a 90.5% detection rate and the 14-pattern, which includes all the biopsies used in the patterns above, only added 1 additional positive case (99.5%). Transitional zone and seminal vesicle biopsies did not result in a significantly increased detection rate when added to the patterns above. Only one positive model was obtained when the transitional zone biopsies were added. The lateral sextant pattern had a detection rate of 95.5%, and the 4-pattern lateral biopsy protocol had a 93.5% detection rate. CONCLUSIONS: Our results suggest that all the biopsy protocols that use laterally placed biopsies based on the 5-region anatomic model are superior to the routinely used sextant prostate biopsy pattern. Lateral biopsies in the mid and apical zones of the gland are the most important.

Blinded evaluation of reverse transcriptase-polymerase chain reaction prostate-specific antigen peripheral blood assay for molecular staging of prostate cancer.

OBJECTIVES: The reverse transcriptase-polymerase chain reaction (RT-PCR)-prostate-specific antigen (PSA) assay to detect presumed occult micrometastatic prostate cancer has been controversial, and this molecular staging has been thought to be clinically useful by some groups but not others. METHODS: We used a sensitive nested RT-PCR assay with specific primers derived from the PSA sequence and a very stringent two-step PCR protocol with denaturing temperature of 94 degrees C annealing and extension temperature of 68 degrees C. This method enabled us to detect PSA-expressing LNCaP prostate cancer (PC) cells as low as one cell of 10 million lymphocytes (1/10(7)). Ninety-six patients with PC were studied, including 85 before radical prostatectomy (RP), and 22 controls, including healthy men and women and men with benign prostatic hyperplasia. RESULTS: In 85 patients undergoing RP, a minimum of two independent RT-PCR-PSA assays detected circulating prostate cells preoperatively in 27 patients (31.8%). Of 12 patients with locally advanced or advanced stage cancer, RT-PCR-PSA was positive in 5 (41.7%); of the 22 controls, no patient was RT-PCR-PSA positive. In 10 randomly selected cases, the RT-PCR product was confirmed as PSA by DNA sequencing. Of the 27 patients undergoing RP who were RT-PCR positive, 11 (40.7%) had non-organ-confined disease (pT3a or greater), and of the 58 patients who were RT-PCR negative, 32 (55.2%) had non-organ-confined disease. Patients with RT-PCR positive results also had lower margin positivity (9 of 27, 33.3%) than did patients with RT-PCR negative results (21 of 58, 36.2%). Finally, at a mean follow-up of 25.7 months, 5 (18.5%) of 27 RT-PCR positive patients had recurrence (PSA) compared with 14 (24.1%) of 58 RT-PCR negative patients. CONCLUSIONS: On the basis of this blinded study, RT-PCR for PSA-expressing cells in 85 patients before RP is not related to clinical stage, age, race, grade, Gleason sum, serum PSA or prostatic acid phosphatase, tumor volume, or tumor multifocality. RT-PCR positivity did not predict pathologic stage or early PSA recurrence. A standardized RT-PCR assay needs to be developed to account for interlaboratory discrepancies.

Detection of circulating prostate specific antigen expressing prostatic cells in the bone marrow of radical prostatectomy patients by sensitive reverse transcriptase polymerase chain reaction.

PURPOSE: The reverse transcriptase polymerase chain reaction (RT-PCR) assay for prostate specific antigen (PSA) expressing cells in the blood circulation has been under intense investigation since 1992. Although it has been suggested that this technology could be used as molecular staging for occult prostatic hematogenous metastases, we have been unable to confirm RT-PCR PSA positivity of peripheral blood to predict stage or recurrence in radical prostatectomy cases. We performed bone marrow RT-PCR PSA assay on a large cohort of radical prostatectomy cases and evaluate the use of this assay in improving prostate cancer staging and detecting early recurrence. MATERIALS AND METHODS: Unilateral anterior iliac crest bone marrow aspirates were performed on 116 patients immediately before radical prostatectomy between February 1995 and September 1997. Radical prostatectomy specimens were processed as whole mounts. A sensitive nested RT-PCR assay with specific primers derived from the PSA sequence was used, which enabled us to detect PSA expressing LNCaP prostate cancer cells at the sensitivity of 1 cancer cell per 10 million lymphocytes (1/10(7)). A minimum of 3 RT-PCR PSA reactions were performed on all patients and at least 2 positive tests were required to define positivity. Patients were followed for PSA recurrence (mean followup 14.7 months). RESULTS: PSA expressing cells were detected in bone marrow of 51 of 116 patients (44.0%) when at least 2 of 3 RT-PCR PSA assays per patient were positive. A much higher rate of RT-PCR PSA positivity was noted (77/116 patients, 66.3%) when any RT-PCR PSA positivity was considered. In 10 randomly selected cases the RT-PCR product was confirmed as PSA by deoxyribonucleic acid sequencing. Of 51 bone marrow RT-PCR positive cases 25 (49%) had organ confined disease and 26 (51%) had nonorgan confined disease. Similarly, bone marrow RT-PCR PSA was not associated with age, race, grade, pretreatment PSA or prostatic acid phosphatase value, clinical stage or margin status. However, the 2-year disease-free survival was 96.6% in RT-PCR negative patients versus 77.5% in RT-PCR positive patients (p = 0.054), and bone marrow RT-PCR PSA was an independent prognostic factor in multivariate analysis including PSA, Gleason grade and pathological stage. CONCLUSIONS: Bone marrow RT-PCR PSA positivity in this study did not predict pathological stage, grade or margin positivity as determined from whole mount prostate cancer specimens. Furthermore, no relationship with age, grade or serum markers and bone marrow RT-PCR PSA positivity was noted. However, bone marrow RT-PCR PSA was associated with early disease recurrence. Further studies and longer followup are warranted to define the metastatic potential of the PSA expressing cells in the bone marrow of prostate cancer patients.

Prostate-specific antigen to predict outcome of external beam radiation for prostate cancer: Walter Reed Army Medical Center experience, 1988-1995.

OBJECTIVES: To assess the ability of pretreatment and post-treatment prostate-specific antigen (PSA) measurements, clinical tumor stage, tumor grade, Gleason sum, race, age, and radiation dose to predict the recurrence of prostate cancer following external beam radiation therapy (XRT) since the introduction of PSA as a tumor marker at one tertiary care center. METHODS: The recurrence of prostate cancer among 371 evaluable patients of 389 patients treated with XRT at Walter Reed Army Medical Center was analyzed using Kaplan-Meier survival methodology and Cox multivariable regression models. Serologic (PSA) recurrence was determined using three consecutive rises in PSA after a nadir value. Clinical recurrence was defined as local recurrence (palpable or positive biopsy) and/or distant (radiographically evident) recurrence. Mean and median follow-up is 40.2 and 39.4 months, respectively (range 3.0 to 89.5), and minimum follow-up is 18 months for patients who were alive at the time of analysis. No patient received adjuvant hormonal therapy. Potential prognostic factors evaluated are pretreatment PSA, PSA nadir, age, race, clinical tumor stage, tumor grade, Gleason sum, and radiation dose. RESULTS: Of the 371 evaluable patients, 125 had disease recurrence. The Kaplan-Meier 5-year disease-free survival (DFS) rates for significant pretreatment variables in univariate analyses are as follows: pretreatment PSA less than 4 (79%), 4.1 to 10 (67%), 10.1 to 20 (57%), 20.1 to 50 (27%), and more than 50 (0%); for clinical tumor Stage T1a-T1c (84%), T2a-T2c (51 %), and T3-T4 (29%); for tumor grade well (58%), moderate (58%), and poor (30%). Four-year DFS rates for Gleason sum are 2 to 4 (82%), 5 (72%), 6 (56%), and 7 to 10 (48%). In multivariable Cox regression analysis with backward elimination of nonsignificant variables, age, race, tumor grade, and radiation dose were eliminated, leaving pretreatment PSA, clinical tumor stage, and Gleason sum as significant prognostic factors. Analysis of a Cox model that included nadir PSA as a time-dependent variable showed it to be the strongest prognostic factor variable in the analysis. CONCLUSIONS: XRT remains a suitable treatment modality for patients with pretreatment PSA less than 20.0, clinical tumor Stages T1-T2, and Gleason sum 2 to 6 prostate cancer. Patients achieving a nadir value less than 0.5 have more durable treatment outcomes.

Statistical modeling using preoperative prognostic variables in predicting extracapsular extension and progression after radical prostatectomy for prostate cancer.

OBJECTIVE: To predict the risk of extracapsular extension and postoperative recurrence before radical prostatectomy (RP) for prostate cancer. METHODS: We performed multivariate Cox regression analysis on preoperative variables in 260 clinically localized prostate cancer patients who underwent RP. With these data, we constructed a relative risk of recurrence (Rr) equation and an equation to predict the probability of extracapsular extension (PECE) before RP. RESULTS: Rr is calculated as exp[(0.47 x race + 0.14 x PSAST) + (0.13 x worst biopsy Gleason sum) + (1.03 x stage T1c) + (1.55 x stage T2b,c)], where PSAST indicates a sigmoidal transformation of prostate-specific antigen. PECE is calculated as 1/[1 + exp(-Z)], where Z = -2.47 + 0.15 (PSAST) + 0.31 (worst biopsy Gleason sum) + 0.18 (race) + 0.16 (stage T1c) + 0.38 (stage T2b,c). CONCLUSION: These two equations can be used preoperatively to predict the probability of extracapsular disease and the risk of prostate-specific antigen recurrence in patients undergoing RP.

CD34 immunohistochemical assessment of angiogenesis as a prognostic marker for prostate cancer recurrence after radical prostatectomy.

PURPOSE: We assess the neovascularity of clinically localized prostate cancer by immunohistochemistry using the monoclonal antibody CD34 in an attempt to identify associations between angiogenesis and disease progression following radical prostatectomy. MATERIALS AND METHODS: Microvascularity was evaluated using the CD34 monoclonal antibody in archival paraffin embedded radical prostatectomy specimens from 149 patients followed from 3 to 10 years (mean 6.6). Vessels were quantified by counting a minimum of 2 selected microscopic fields (200x, 0.754 mm.2) from each tumor, area of prostatic intraepithelial neoplasia and prostatic hyperplasia, and given a numerical value representing the microvessel density count. RESULTS: Mean microvessel density count did not vary significantly with age or race. There was a significant association between the count and nuclear grade, Gleason sum and pathological stage. Cox survival analysis shows that microvessel density is significantly related to time to recurrence when considered as a continuous variable (p=0.03) as well as dichotomous variable (p=0.007) (microvessel density count less than 90 and 90 or greater). The 5-year recurrence-free survival was significantly higher for patients with a count less than 90 (71%) than for those with a count 90 or greater (51%) (p=0.006). The 5-year recurrence-free survival was also significantly different when microvessel density was used as a continuous variable (p=0.02). Controlling for stage, Gleason sum, race and nuclear grade, microvessel density remained significant in predicting recurrence (p=0.03) but when pretreatment prostate specific antigen was included in the model the count was no longer significant. The microvessel density count in the tumor area significantly increased with increasing Gleason sum and nuclear grade but it did not increase significantly in the adjacent benign prostate or areas of prostatic intraepithelial neoplasia in the same specimen. CONCLUSIONS: Microvascularity or neovascularity as measured by the CD34 antigen may be a prognostic marker of recurrence for prostate cancer patients after radical prostatectomy but more study in prostate specific antigen era patients with sufficient followup is needed.