DIGITAL RECTAL EXAMINATION AND IMAGING STUDIES ARE UNNECESSARY IN MEN WITH UNDETECTABLE PROSTATE SPECIFIC ANTIGEN FOLLOWING RADICAL PROSTATECTOMY

PURPOSE: We determine the probability of local or distant recurrence following radical prostatectomy in men with an undetectable prostate specific antigen (PSA) level. MATERIALS AND METHODS: The clinical course of 1,916 consecutive men followed during a 14-year period after radical prostatectomy was reviewed. Average followup plus or minus standard deviation is 5.5+/-3.5 years, and 326 men (17%) have been followed for more than 10 years. In total this population of men has been followed for 10,540 patient-years. RESULTS: Of 1,916 men 56 (2.9%) had local recurrence an average of 6.1+/-2.7 years (range 1 to 12) after surgery. No man had local recurrence with an undetectable serum PSA. Mean serum PSA at the time of local recurrence was 5.8 ng./ml. Of the 56 men 13 (25%) who had local disease recurrence had an undetectable serum PSA at 5 years of followup but had progression to biochemical and local disease recurrence later. Of 1,916 men 118 had distant metastases with a mean serum PSA of 28.6 ng./ml. No man has had distant metastasis with an undetectable serum PSA. CONCLUSIONS: Disease can recur after radical prostatectomy even after an extended biochemical disease-free interval. None of the 1,916 men followed for an average of greater than 5 years after surgery had local recurrence or distant metastasis with an undetectable serum PSA. Based on these observations, we recommend no further evaluation, that is digital rectal examination or imaging studies, in men with an undetectable PSA following radical prostatectomy.     

Prostate Specific Antigen Density of the Transition Zone: A New Effective Parameter for Prostate Cancer Prediction

Purpose

Use of prostate specific antigen (PSA) density to enhance the predictive value of detecting prostate cancer at intermediate PSA levels has been limited due to contradictory results in large scale studies. Most PSA leakage from the benign prostate into the serum comes from the transition zone. Therefore, in patients with benign prostatic hyperplasia (BPH) and prostate cancer with a serum PSA of less than 10 ng./ml. we studied and compared the values of PSA density of the total prostate and the transition zone. We examined the ability of PSA density of the transition zone to enhance prostate cancer detection in patients with intermediate PSA levels.

Materials and Methods

The volumes of the entire prostate and of the transition zone were determined by transrectal ultrasound. PSA density for both regions was calculated in 88 patients with histologically confirmed prostate cancer (radical prostatectomy), and 74 with BPH and histologically proved benign disease.

Results

Average total prostate PSA density plus or minus standard deviation was 0.12 +/− 0.07 and 0.22 +/− 0.12 ng./ml./cc in patients with BPH and prostate cancer, respectively, while average PSA density of the transition zone was 0.21 +/− 0.13 and 1.02 +/− 0.70 ng./ml./cc, respectively (p <0.0001). If a total prostate PSA density of 0.15 had been chosen, the cancer would have been missed in 34% of the patients compared to 10% if a cutoff value of 0.35 for PSA density of the transition zone had been chosen (p <0.001). Overall, in patients with a PSA of 0.25 to 10.0 ng./ml. the sensitivity and specificity of PSA density of the transition zone for predicting prostate cancer at a 0.35 cutoff value were 90 and 93%, respectively, compared to 94 and 89%, respectively, for those with a PSA of 4 to 10 ng./ml.

Conclusions

In our study PSA density of the transition zone was much more accurate in predicting prostate cancer than was total prostate PSA density for PSA levels of less than 10 ng./ml. With respect to the high sensitivity and specificity, if confirmed in large prospective studies, including patients seen for early diagnosis, PSA density of the transition zone could become a routine tool for urologists in the prediction of prostate cancer in men with a PSA of 4 to 10 ng./ml.     

THE EFFECT OF HIGH GRADE PROSTATIC INTRAEPITHELIAL NEOPLASIA ON SERUM TOTAL AND PERCENTAGE OF FREE PROSTATE SPECIFIC ANTIGEN LEVELS

PURPOSE: It is established that the percentage of free prostate specific antigen (PSA) in serum is low in patients with prostate cancer. An unanswered question is whether a low percentage of free PSA can be explained by high grade prostatic intraepithelial neoplasia alone. We compared the percentage of free PSA in men with high grade prostatic intraepithelial neoplasia alone, prostate cancer, benign prostatic hyperplasia (BPH) and a normal prostate (that is normal digital rectal examination and PSA less than or equal to 2.5 ng./ml.). MATERIALS AND METHODS: From October 1994 through December 1997, 48 men were diagnosed with high grade prostatic intraepithelial neoplasia without concomitant prostate cancer. Of these men 43 with a mean age plus or minus standard deviation of 67.4 +/- 7.8 years comprised our study group. To date none has been diagnosed with cancer during followup. Serum free and total PSA levels were measured, and the percentage of free PSA was calculated. The percentage of free PSA in the 43 men was compared to that in 50 with prostate cancer (mean age 65.4 +/- 7.8 years), 50 with biopsy proved BPH (67 +/- 7) and 43 with a normal prostate (61 +/- 8). RESULTS: There was no significant difference in mean total serum PSA in patients with high grade prostatic intraepithelial neoplasia, prostate cancer or BPH. The percentage of free PSA was significantly lower in patients with prostate cancer (14.9 +/- 6.5%) than those with high grade prostatic intraepithelial neoplasia (20.8 +/- 7.1%), BPH (20.1 +/- 7.3%) or a normal prostate (27.7 +/- 12.2%). There was also no significant difference in the percentage of free PSA between men with high grade prostatic intraepithelial neoplasia (20.8 +/- 7.1%) and those with BPH (20.1 +/- 7.3%). Additionally, men with a normal prostate had a higher percentage of free PSA (27.7%) than those with BPH (20.1%), high grade prostatic intraepithelial neoplasia (20.8%) or prostate cancer (14.9%). CONCLUSIONS: The percentages of free PSA in men with high grade prostatic intraepithelial neoplasia and BPH are similar, and significantly higher than those found in men with prostate cancer.     

Insulin-like growth factor-1 and insulin-like growth factor binding protein-3 for prostate cancer detection in patients undergoing prostate biopsy

PURPOSE: Laboratory and epidemiological studies suggest that high circulating insulin-like growth factor (IGF)-1 and low IGF binding protein-3 are associated with increased prostate cancer risk. However, the usefulness of serum IGF-1 or IGF binding protein-3 for predicting pathology results in men undergoing prostate biopsy is unclear. We examined the relationships of serum IGF-1, IGF binding protein-3 and the results of prostate biopsy. MATERIALS AND METHODS: A total of 652 consecutive patients with elevated serum prostate specific antigen (PSA) or abnormal digital rectal examination who were referred for transrectal ultrasound sextant prostate needle biopsy underwent blood sampling before biopsy. PSA, free PSA, IGF-1 and IGF binding protein-3 were measured. There were 244 men (37.4%) with cancer and 408 controls with benign conditions. RESULTS: Mean IGF-1 plus or minus SD in the cancer and control groups was 176.1 +/- 58.3 and 178.7 +/- 54.7 ng./ml., respectively (p = 0.57). Mean IGF binding protein-3 in the cancer and control groups was 2,724 +/- 647 and 2,673 +/- 589 ng./ml., respectively (p = 0.3). Adjustment for age and PSA showed significantly lower IGF-1 in cancer cases, while IGF binding protein-3 was not significant. ROC values were significantly higher for free-to-total PSA and PSA than for crude and age adjusted IGF-1 and IGF binding protein-3. CONCLUSIONS: Our data indicate that serum IGF-1 or IGF binding protein-3 does not predict the results of prostate biopsy in men with elevated PSA or abnormal digital rectal examination. This finding implies that while there is evidence that the IGF-1 level is a risk factor for prostate cancer, neither IGF-1 nor IGF binding protein-3 can be used as a tumor marker for this disease.     

EVALUATION OF CHANGES IN PROSTATE SPECIFIC ANTIGEN IN CLINICALLY LOCALIZED PROSTATE CANCER MANAGED WITHOUT INITIAL THERAPY

Purpose

We define changes in prostate specific antigen (PSA) measurements with time in 49 men 71.9 +/− 7.0 years old (mean plus or minus standard deviation) with clinically localized prostate cancer who remain untreated.

Materials and Methods

We retrospectively analyzed PSA changes in prostate cancer patients managed by watchful waiting. In all patients a minimum of 3 PSA levels were measured at intervals of at least 6 months after malignancy was diagnosed. The rate of change in serum PSA level with time (PSA velocity) was determined using an exponential, log linear model.

Results

In 49 patients treated conservatively mean initial PSA level plus or minus standard deviation was 12.3 +/− 11.1 ng./ml. and mean PSA followup during which no therapy for prostate cancer was introduced was 32.1 +/− 13.2 months. PSA levels decreased during the observation period in 11 of the 49 patients (22%) and median PSA doubling time in the remaining 38 was 55.7 months (range 15.1 to 994.5). There was no significant correlation between age at diagnosis, Gleason sum, initial PSA level or clinical stage and PSA velocity. The short-term rate of change in PSA during the first 9 months after prostate cancer was diagnosed correlated poorly with overall PSA velocity. The short-term rate of PSA change was greater than the overall rate of change in 14 of 37 patients (38%).

Conclusions

There is significant variability in the rate of change of PSA with time in men with clinically localized prostate cancer who remain untreated. The usefulness of serial PSA measurements in the management of watchful waiting is unclear. Changes in PSA may not be helpful or appropriate in determining the need for therapy after a period of observation.     

PROSTATE-SPECIFIC ANTIGEN IN MASS SCREENING FOR CARCINOMA OF THE PROSTATE

Background:
Prostate-specific antigen (PSA) has various advantages over prostatic acid phosphatase (PAP) as a marker for prostate cancer, but its role in prostate cancer mass screening remains controversial. We measured serum PSA in addition to serum PAP determination and digital rectal examination (DRE) in our mass screening program to assess the usefulness of PSA for prostate cancer mass screening.
Methods:
Serum PSA and PAP measurements and DRE were performed in 1249 patients in mass screening for carcinoma of the prostate in 1989 and 1990. Thirteen cancers were diagnosed. We calculated the mean plus standard deviations (2SD) of the PSA and PAP values of men without cancer, and assessed the usefulness of PSA for prostate cancer screening by using these figures as the upper limit of normal.
Results:
The number positive for PSA, PAP and DRE were 39, 36 and 48, respectively. If our screening had been performed without DRE, three cancers would have remained undetected, and the number would have been the same if performed without PSA. If the screening had been performed without PAP, on the other hand, no cancers would have remained undetected. The sensitivities of PSA and PAP were 54% and 23%, respectively. The screening detection rate with DRE and PSA was 0.88%, and with DRE and PAP was 0.64%.
Conclusions:
Measurement of serum PSA values with adjustment of the cut-off value was considered more useful than PAP in mass screening for prostate cancer.     

Serum prostate specific antigen is a strong predictor of future prostate growth in men with benign prostatic hyperplasia. PROSCAR long-term efficacy and safety study

PURPOSE: We analyze patterns of prostate growth in men diagnosed with benign prostatic hyperplasia (BPH) and treated with placebo during 4 years, and determine which baseline parameters were the strongest predictors of growth. MATERIALS AND METHODS: A total of 3,040 men were enrolled in the 4-year randomized, placebo controlled Proscar Long-Term Efficacy and Safety study. Of these men a subgroup of 10% underwent pelvic magnetic resonance imaging prostate volume measurement at baseline and yearly thereafter. Absolute and percent volume changes during 4 years were calculated in the 164 placebo treated men in the subgroup. The ability of age, baseline prostate volume and prostate specific antigen (PSA) to predict prostate growth in placebo treated patients was assessed by multiple linear regression analyses, receiver operator characteristics curves, and evaluations of growth stratified by tertiles of baseline serum PSA and decades of life. RESULTS: In placebo treated patients a steady increase in mean plus or minus standard deviation prostate volume from year to year was noted (2.5+/-6.1, 4.9+/-6.8, 6.4+/-8.5 and 7.2+/-8.8 ml. at years 1, 2, 3 and 4, respectively). Mean volume changes at 4 years ranged from -9 to +30 ml. Mean percent change from baseline ranged from 12.5% to 16.6% for men 50 to 59 years old to those 70 to 79 years old. Baseline serum PSA was a strong predictor of growth with 7.4% to 22.0% change at 4 years from the lowest to highest PSA tertiles. Annualized growth rates from baseline were 0.7 ml. per year for PSA 0.2 to 1.3, 2.1 for PSA 1.4 to 3.2 and 3.3 for PSA 3.3 to 9.9 ng./ml. Multiple linear regression analysis showed that serum PSA was a stronger predictor of prostate growth than age or baseline prostate volume. All but 1 man with baseline serum PSA greater than 2.0 ng./ml. had prostate growth during 4 years, and 32.6% of men with serum PSA less than 2.0 exhibited a decrease in volume. CONCLUSIONS: Serum PSA is a stronger predictor of growth of the prostate in placebo treated patients than age or baseline prostate volume. Since prostate volume is a risk factor for acute urinary retention and the need for BPH related surgery, the ability of PSA to predict prostate growth may be an important factor when considering individual treatment options for BPH. Such use of PSA represents a shift in paradigm away from focusing solely on symptoms of BPH toward a more comprehensive approach with consideration of predicting and preventing risk factors of BPH related outcomes.     

Daily variability in human serum prostate-specific antigen and prostatic acid phosphatase: a comparative evaluation

The daily variation of serum levels of prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) was investigated simultaneously in 10 patients with osseous metastatic prostatic cancer, 10 patients with benign prostatic hyperplasia, and 10 volunteers without prostatic disease. Duplicate serum samples were obtained from all patients on the same day at 8 AM, 12 PM, 4 PM, and 8 PM. Statistical analysis (two-factor analysis of variance comparing time period to disease group) of the mean PSA and PAP levels at the four sampling times on all patient groups demonstrated no evidence of circadian rhythmic variation or any other distinct pattern for the observed sample times. Overall, the variability in PSA levels was significantly less than that observed for PAP. There was no significant difference in mean percent variation between patient groups (cancer, benign, and normal prostate glands) for both the PSA and PAP assays. Our data reveal that serum PSA measurements fluctuate unpredictably over the course of a day in patients with and without prostatic disease, but to a lesser extent than that seen for serum PAP values. These findings illustrate the potential inaccuracy of single determinations of serum PAP or PSA levels for monitoring disease recurrence and treatment response in patients with prostate cancer.     

Pretreatment serum testosterone level as a predictive factor of pathological stage in localized prostate cancer patients treated with radical prostatectomy

OBJECTIVE: Pretreatment serum level of testosterone (T) is a potential prognostic factor for prostate cancer. The present study was conducted to evaluate the clinical significance of pretreatment serum T level in patients with clinically localized prostate cancer. MATERIALS AND METHODS: The subjects were 82 clinically localized prostate cancer patients treated with radical prostatectomy, whose pretreatment T levels were recorded. We investigated clinical and pathological factors such as pretreatment serum T level, age, pretreatment PSA or pathological Gleason score concerning the association with pathological stage and biochemical recurrence. RESULTS: The mean pretreatment T level was significantly lower in patients with non-organ-confined prostate cancer (pT3-T4, N1; 3.44+/-1.19 ng/ml) than in patients with organ-confined cancer (pT2; 4.33+/-1.42 ng/ml) (p=0.0078). Multivariate analysis demonstrated that pathological Gleason score, pretreatment serum T level and pretreatment PSA were significant predictors of extraprostatic disease. When the patients were divided into high and low T level groups according to the median value, pretreatment T levels were not significantly associated with PSA recurrence rates (p=0.7973). CONCLUSIONS: A lower pretreatment T level appears to be predictive of extraprostatic disease in patients with localized prostate cancer.     

Predicting radionuclide bone scan findings in patients with newly diagnosed, untreated prostate cancer: prostate specific antigen is superior to all other clinical parameters.

Presently, the standard staging evaluation of prostate cancer includes digital rectal examination, measurement of serum tumor markers and a radionuclide bone scan. To evaluate the ability of local clinical stage, tumor grade, serum acid phosphatase, serum prostatic acid phosphatase (PAP) and serum prostate specific antigen (PSA) to predict bone scan findings, a retrospective review of 521 randomly chosen patients (mean age 70 years, range 44 to 92 years) with newly diagnosed, untreated prostate cancer was performed. Local clinical stage, tumor grade, acid phosphatase, PAP and PSA all correlated positively with bone scan findings (p less than 0.0001). Using receiver operating characteristic curves, however, PSA had the best over-all correlation with bone scan results. The median serum PSA concentration in patients with a positive bone scan was 158.0 ng./ml., whereas men with a negative bone scan had a median serum PSA level of 11.3 ng./ml. (p less than 0.0001). Using multivariate logistic regression analysis, local clinical stage, tumor grade, acid phosphatase and PAP were evaluated in combination with PSA to assess whether these parameters increased the ability of PSA alone to predict bone scan findings. None of these clinical parameters, irrespective of the combination used, contributed appreciably to the predictive power of PSA alone. A probability plot with 95% confidence intervals was constructed that allows the practicing urologist to estimate on an individual basis the probability of a positive bone scan for any given serum PSA value. The most significant finding of this study, however, was the negative predictive value of a low serum PSA concentration for bone scan findings. In 306 men with a serum PSA level of 20 ng./ml. or less only 1 (PSA 18.2 ng./ml.) had a positive bone scan (negative predictive value 99.7%). This finding would suggest that a staging radionuclide bone scan in a previously untreated prostate cancer patient with a low serum PSA concentration may not be necessary.     

Retrospective comparison of radical retropubic prostatectomy and 125iodine brachytherapy for localized prostate cancer

PURPOSE: Favorable results with 125iodine (I) brachytherapy have been reported in select patients with localized prostate cancer. We evaluate the results of radical prostatectomy in patients matched for similar pretreatment clinicopathological characteristics. MATERIALS AND METHODS: From May 1983 to April 1998, 1 surgeon (W. J. C.) performed radical retropubic prostatectomy in 1,952 men (mean age plus or minus standard deviation 63+/-7 years), of whom 1,364 had Gleason score 6 or less on preoperative needle biopsy, a preoperative serum prostate specific antigen (PSA) value available and clinical stage T1 or T2 disease. We categorized all patients by preoperative Gleason score, preoperative PSA and clinical stage. For each Gleason score-by-PSA stratum we randomly selected by computer the number of men necessary to achieve the same overall distribution of clinical characteristics as in a series of patients treated with brachytherapy. All men were followed with semiannual PSA measurements and annual digital rectal examinations. Serum PSA greater than 0.3 ng/ml was considered evidence of cancer recurrence. Simple univariate statistics were used to compare clinical characteristics between series, and 7-year recurrence-free survival was estimated using Kaplan-Meier product limit estimates. To avoid a possible chance extreme result from 1 random sample we estimated 7-year recurrence-free survival in 5 computer selected random samples of our population. RESULTS: Mean 7-year recurrence-free survival was 84% (95% confidence intervals 78 to 89) for the radical prostatectomy series compared to 79% (confidence intervals not provided) for the 125I brachytherapy series. CONCLUSIONS: Radical prostatectomy yielded a proportionately but not statistically significant higher 7-year probability of nonprogression than 125I brachytherapy in patients with favorable clinicopathological characteristics. Comparisons are confounded by residual differences in clinicopathological features of tumors between groups and different treatment end points to determine outcomes. Further prospective, randomized clinical trials are required for valid comparisons.     

Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia

OBJECTIVES: To assess the utility of prostate-specific antigen (PSA) as a predictor of prostate volume by characterizing the relationship between prostate volume and serum PSA in men with symptomatic benign prostatic hyperplasia (BPH) and no evidence of prostate cancer, stratified by decade of life. METHODS: Placebo-controlled multicenter trials in patients with BPH and a safety study in normal young men provided baseline measurements of serum PSA and prostate volume. The analyses included patients with a baseline prostate volume measured by either transrectal ultrasound (TRUS) or magnetic resonance imaging and baseline serum PSA. A common central laboratory was used for all but one of the individual studies; both laboratories used the Hybritech method. Patients 80 years of age or older were excluded. Patients with a baseline serum PSA greater than 10 ng/mL were excluded to reduce the likelihood of including occult prostate cancer cases. The patients in the BPH trials were screened at baseline by digital rectal examination (DRE) and serum PSA. Those with suspicious findings underwent TRUS-guided biopsy; only patients with negative biopsies are included in these analyses. RESULTS: The analyses included 4627 patients, 4448 from the BPH trials and 179 from the safety study. The men in the BPH trials were older (mean age+SE, 63.7+0.10 years) than the men in the safety study (mean age + SE, 30.8+/-0.43), had larger prostates (mean volume+/-SE, 43.7+/-0.38 mL versus 26.3+/-0.49 mL in the safety study), and had higher serum PSA values (mean+/-SE, 2.6+/-0.03 ng/mL versus 0.7+/-0.39 ng/mL in the safety study). The relationship between prostate volume and serum PSA was evaluated using only the BPH trial data. Prostate volume and serum PSA have an age-dependent log-linear relationship (ie, their logarithms are linearly related, and the parameters of the relationship depend on age). Older men tend to have a steeper rate of increase in prostate volume with increasing serum PSA (P < 0.00 for differences between slopes), and there was a slight tendency for PSA density to increase with age. Receiver operating characteristic (ROC) curves were constructed to evaluate the ability of serum PSA to predict threshold prostate sizes in men with BPH. The ROC curve analyses revealed that PSA had good predictive value for assessing prostate volume, with areas under the curve ranging from 0.76 to 0.78 for various prostate volume cutoff points (30, 40, and 50 mL). Conclusions. Prostate volume is strongly related to serum PSA in men with BPH and no evidence of prostate cancer, and the relationship depends on age. Since treatment outcome or risk of long-term complications depend on baseline prostate volume, serum PSA can estimate the degree of prostate enlargement sufficiently accurately to be useful for therapeutic decision making. To achieve a specificity of 70% while maintaining a sensitivity between 65% and 70%, approximate age-specific criteria for detecting men with prostate glands exceeding 40 mL are PSA > 1.6 ng/mL, >2.0 ng/mL, and >2.3 ng/mL for men with BPH in their 50s, 60s, and 70s, respectively.     

Multicenter, randomized, double-blind, placebo controlled study to investigate the effect of finasteride (MK-906) on stage D prostate cancer.

A total of 28 untreated patients with asymptomatic, stage D prostate cancer was randomized in a double-blinded fashion to receive finasteride (10 mg. per day), a 5 alpha-reductase inhibitor or placebo. Patients were evaluated at 3-week intervals by rectal examination, and serum prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) levels, and at 6-week intervals by bone scan and transrectal ultrasound determinations of prostatic volume. Patients stopped the medication at week 6 at the discretion of the investigator when PSA levels increased from baseline. After 12 weeks all patients were reevaluated. Of the patients 13 received finasteride and 15 received placebo. The 2 groups did not differ statistically with respect to patient age, initial PSA and PAP level, or the extent of metastases on initial bone scan. A statistically significant decrease in the median percentage change from baseline in PSA at weeks 3 and 6 occurred in the finasteride group compared to the placebo group (-22.9% versus -2.9% and -15.1% versus +11.7%, respectively, p less than 0.05). Finasteride had no effect upon PAP, serum testosterone, prostatic volume or appearance of bone scans. A decrease in serum PSA in the finasteride treatment group suggests that finasteride exerts a minor effect in patients with prostate cancer. This effect does not approach that seen with medical or surgical castration yet because of the potency preserving feature and the lack of toxicity finasteride may warrant further study in the treatment of prostate cancer.     

A comparison of the free fraction of serum prostate specific antigen in men with benign and cancerous prostates: the best case scenario

Purpose

In most previous studies of free-to-total serum prostate specific antigen (PSA) ratios, the specimens from patients with prostate cancer or those with benign prostatic hyperplasia (BPH) have not been highly characterized. We compared preoperative sera from post-radical prostatectomy patients with clinically significant cancers of at least 2 cm.³ to sera from those with BPH and large, biopsy negative prostates.

Materials and Methods

We used 2 different time resolved immunofluorometric assays for free and total PSA, and a combination of a chemoluminescent immunoassay for free PSA detection with an immunoradiometric assay for total PSA to measure free and total PSA. The serum ratios of free-to-total PSA in these assays were compared to those obtained previously from gel filtration studies. Sera from 51 men with prostate cancer volumes of 2 to 18 cm.³ were compared to those from 48 men with BPH and a mean prostate volume of 78 plus/minus 7 cm.³. The respective mean serum PSA levels plus or minus standard deviation were 10.0 plus/minus 6.3 and 8.9 plus/minus 7.2 ng./ml.

Results

Monoclonal assays for free PSA confirmed the previous study with gel filtration. For PSA 4 to 10 ng./ml., 94 to 95 percent of the men with prostate cancer were correctly diagnosed, with a cutoff of less than 15 percent for free-to-total PSA on immunofluorometric assay and less than 14 percent for chemoluminescent immunoassay with immunoradiometric assay. However, 46 percent (immunofluorometric assay) and 36 percent (chemoluminescent immunoassay and immunoradiometric assay) of men with BPH did not have enough free PSA for diagnosis of BPH (that is 36 to 46 percent false-positive rate).

Conclusions

For total PSA 4 to 10 ng./ml., the sensitivity of approximately 15 percent free-to-total PSA for prostate cancer is high (94 to 95 percent) but 36 to 46 percent of men with BPH and a large gland will not be correctly identified. For PSA 2 to 4 ng./ml., no ratio of percent free-to-total PSA discriminated BPH from prostate cancer.     

Benefit of adjuvant radiation therapy for localized prostate cancer with a positive surgical margin

PURPOSE: Positive surgical margins are common after radical prostatectomy, and the role of adjuvant therapy in such cases is controversial. We determined the benefit of postoperative external beam radiation therapy in patients with margin positive prostate cancer with respect to biochemical progression or cancer recurrence. To decrease confounding factors that may affect the likelihood of biochemical progression our study was limited to men with organ confined cancer and a single positive margin. MATERIALS AND METHODS: We retrospectively evaluated the records of a nested matched cohort of 76 patients with pathological stage T2N0 prostate cancer and a single positive margin who underwent adjuvant radiation therapy within 3 months of radical prostatectomy. There was a positive margin at the prostatic apex in 35 cases, prostatic base in 18, posterior prostate in 11, urethra in 7, and prostatic apex and urethra in 5. These patients were matched 1:1 with 76 controls who did not receive adjuvant radiation therapy. Neither group received androgen deprivation therapy. Patients and controls were matched exactly for the margin positive site, age at surgery, preoperative serum prostate specific antigen, Gleason score and DNA ploidy. Biochemical relapse was defined as posttreatment PSA greater than 0.2 ng./ml. RESULTS: Overall there was significant estimated improvement plus or minus standard error in 5-year clinical and biochemical progression-free survival in 88%+/-5% versus 59%+/-11% of patients treated with adjuvant radiation therapy versus no radiation therapy (p = 0.005). No patient who received radiation therapy had local or distant recurrence, while 16% of controls had recurrence (p = 0.015). When stratified by site of margin positivity, the 5-year estimated clinical and biochemical progression-free rate in 18 cases and controls with a positive base margin was 95%+/-15% and 65%+/-13%, respectively (p = 0.02). The rate in 35 cases and cases with a positive apex margin was 95%+/-5% and 64%+/-15%, respectively (p = 0.07). Limited sample size precluded analysis of the other sites. CONCLUSIONS: Patients with localized prostate cancer and a singe positive surgical margin appear to have a lower rate of biochemical relapse at 5 years when adjuvant radiation therapy is administered. Definitive evidence of the beneficial effect of adjuvant radiation therapy for patients with involved surgical margins awaits conclusion of randomized clinical trials.     

Prostate specific antigen--a screening test for prostatic cancer?

A series of 287 patients referred by their family doctors with symptoms of bladder outflow obstruction were asked to attend the hospital for "pre-clinic" screening for carcinoma of prostate (CaP). Blood samples were collected from 211 patients and analysed for serum prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). Thirty-six patients had a serum PSA greater than 10 micrograms/l and 7 had PAP levels greater than 5 iu/l. In no instance was the PAP elevated without an associated increase in PSA concentration. Patients with raised markers underwent further investigations which included prostatic biopsy and/or resection; 17 patients were proved to have carcinoma of the prostate, 9 of whom had distant metastases. The specificity of PSA for detecting prostate cancer in this study was 90% with a sensitivity of 89.5%, in contrast to values for PAP of 100% and 36.8%. The routine use of PAP as a marker for prostatic cancer should be abandoned. The use of PSA as a screening test in a group of patients with prostatism appears justified, but with a positive predictive value of only 47%, its use in a mass unselected screening programme is not recommended.     

Comparison of prostate secretory protein with prostate specific antigen and prostatic acid phosphatase as a serum biomarker for diagnosis and monitoring patients with prostate carcinoma

Serum prostate secretory protein (PSP) levels were measured in 49 patients with benign prostatic hyperplasia (BPH), 144 patients with various stages of prostatic carcinoma (CaP), and 82 CaP patients who were followed serially. PSP values were compared with serum levels of prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). In the BPH group, PSP was elevated (> 10 ng/ml) in 41% of patients, whereas PSA (> 4 ng/ml) and PAP (> 3.3 ng/ml) were elevated in 39% and 23% of the cases, respectively. PSP levels were elevated in 48% of the CaP pretreatment specimens, compared to 79% for PSA and 40% for PAP. PSP levels in cancer patients who had intracapsular disease were about two to three times higher than those observed for PAP. PSP was found to be the only marker elevated in eight (6%) pretreatment CaP patient serum specimens, while PAP was never found to be elevated when PSA was normal. PSP serum concentrations correlated with the clinical course of the disease in 79% of patients, compared with 90% for PSA and 66% for PAP. In certain patients, monitored over time, disease correlation was reflected in serum values with only a single biomarker, i.e., 1% with PAP, 8% with PSP, and 10% with PSA. This study has shown that PSP is a less sensitive serum biomarker than PSA, but more sensitive than PAP for detection and monitoring the early stages of prostate cancer. This suggests that PSP as a biomarker may be a useful adjunct for the management of a subpopulation of low-stage and -grade CaP. © 1993 Wilcy-Liss, Inc.     

Prostate specific antigen doubling time after radical prostatectomy: effect of neoadjuvant androgen deprivation therapy

PURPOSE: We determined the predictors of prostate specific antigen (PSA) doubling time in patients with relapse after radical prostatectomy as well as whether PSA doubling time is shorter in those treated versus not treated with neoadjuvant androgen deprivation therapy. MATERIALS AND METHODS: We calculated PSA doubling time in 204 patients with PSA relapse after radical prostatectomy who were or were not treated with neoadjuvant androgen deprivation therapy. Analysis of covariance was used to determine the effect of clinical and pathological parameters on PSA doubling time, and the proportion of variability explained by these parameters. RESULTS: Clinical stage, and combined clinical stage and margin status, clinical stage and androgen deprivation therapy status, androgen deprivation therapy status and time to PSA relapse, and androgen deprivation therapy status and pretreatment PSA were significant predictors of PSA doubling time. Any variable or combination of variables explained up to only 21% of PSA doubling time variability. When stratified by pretreatment PSA, clinical stage and biopsy grade, the difference in doubling times in patients treated with or without neoadjuvant androgen deprivation therapy was significant only for 4.1 to 10 ng./ml. PSA. In this group mean doubling time plus or minus standard deviation in patients receiving neoadjuvant androgen deprivation therapy and those treated only with radical prostatectomy was 7.6+/-1.0 and 15.4+/-2.6 months, respectively. CONCLUSIONS: Our study indicates that it is difficult to predict PSA doubling time in an individual. The small proportion of variability in PSA doubling time explained by the interaction of androgen deprivation therapy status and other variables indicates that these factors are not clinically significant.     

Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience

In a large series of 2404 men with a mean follow-up of 6.3 plus or minus 4.2 years (range, 1-17) after anatomic RRP for clinically localized prostate cancer, 412 men (17%) have recurred. A detectable PSA was the only evidence of recurrence in 9.7%, whereas 1.7% and 5.8% had local recurrence and distant metastasis, respectively. The overall actuarial 5-, 10-, and 15-year recurrence-free survival rates for these men were 84%, 74%, and 66%, respectively. As demonstrated in the authors' previous reports, the actuarial likelihood of a postoperative recurrence increased with advancing clinical stage, Gleason-score, preoperative PSA level, and pathologic stage. Subdivision of men with Gleason 7 tumors resulted in better stratification. There was a similar actuarial likelihood of postoperative recurrence for men with Gleason 4 + 3 and Gleason score 8 to 10 disease. The actuarial rate of recurrence of tumor for men with Gleason 3 + 4 disease was statistically different from the rate for men with Gleason score 6 or Gleason 4 + 3 disease. The overall actuarial metastasis-free survival rates at 5, 10, and 15 years were 96%, 90%, and 82%, respectively. The overall actuarial cancer-specific survival rates at 5, 10, and 15 years were 99%, 96%, and 90%, respectively. This study provides long-term outcome of patients with clinically localized cancer who underwent RRP between 1982 and 1999. Recognizing that this long-term study includes many patients with more advanced disease diagnosed before the PSA era, caution must be exercised in comparing these results with the outcomes for cohorts of patients treated since 1989. Anatomic RRP is an effective way to manage clinically localized prostate cancer. Excellent long-term results can be obtained with RRP for early stage disease. The proportion of men with early stage prostate cancer will continue to increase with wide use of serum PSA testing and digital rectal examination.