STABILITY OF FREE AND TOTAL PROSTATE SPECIFIC ANTIGEN IN SERUM FROM PATIENTS WITH PROSTATE CARCINOMA AND BENIGN HYPERPLASIA

Purpose

Instability of prostate specific antigen (PSA) in serum might complicate the interpretation of the free-to-total PSA ratio. We studied the in vitro stability of free PSA and total PSA in serum of patients with prostate cancer or benign prostate hyperplasia (BPH), and of elderly man without known prostate disease. Furthermore, we investigated conditions to stabilize the in vitro values in serum.

Materials and Methods

The effects of storage at 4C on free and total PSA were investigated in serum of 32 men with prostate cancer, 25 with BPH and 29 older than 70 years. All had total PSA less than 25 micro g./l. The influence of total PSA levels on in vitro changes in free-total PSA was studied in serum of 39 other prostate cancer patients (total PSA 1.7 to 298 micro g./l.). Stabilization studies were performed in yet another series of samples from 54 prostate cancer patients (total PSA 1.3 to 238 micro g./l.) by adjustment of serum pH to 5.5 before storage. Free and total PSA was measured by a commercial immunofluorometric assay, as well as by in-house immunofluorometric assays. Statistical analyses of the results were performed by analysis of variance with repeated measures.

Results

We found no difference between the results obtained by the 2 assay systems. After 7 days at 4C there was a slight decrease in total PSA in sera of prostate cancer patients, BPH patients and men older than 70 years. A decrease in mean free PSA values occurred in all groups (21.3, 15.7 and 14.6%, respectively). The decrease of free PSA with time was significant (p <0.0001) in all groups but there was no significant difference among the groups (p = 0.16). The concomitant decrease in free-to-total PSA ratio was significant in all groups (p <0.0001). This change was group dependent (p = 0.003), with the largest decrease in the prostate cancer group. Large interindividual differences were observed. Storage at 4C for 7 days of sera of 39 patients with localized and disseminated prostate cancer (total PSA 1.7 to 298 micro g./l.) gave a more pronounced decrease in free PSA than in total PSA. Adjustment of serum pH to 5.5 had a stabilizing effect on free PSA and on the free-to-total PSA ratio, giving a significantly smaller change in both values (p <0.0001).

Conclusions

In vitro instability of free PSA in serum and large interindividual differences should be considered when using the ratio of free-to-total PSA in evaluation of patients with suspected prostate cancer. Serum samples should be stored frozen if not analyzed immediately or acidified to pH 5.5. Interpretation of data from determination of free-to-total PSA ratio should be done with caution if the sampling and storage conditions are not known.     

PROSTATIC VOLUME AND RATIO OF FREE-TO-TOTAL PROSTATE SPECIFIC ANTIGEN IN PATIENTS WITH PROSTATIC CANCER OR BENIGN PROSTATIC HYPERPLASIA

Purpose

We correlated prostatic volume with the ratio of free-to-total prostate specific antigen (PSA) in serum from patients with prostatic cancer or benign prostatic hyperplasia (BPH) to evaluate how prostatic volume influences the ratio.

Materials and Methods

We evaluated sera from 395 patients (mean age 65 years, range 45 to 88) with prostate cancer (239) or BPH (156) for total PSA, free PSA and ratio of free-to-total PSA. For detection of total and free PSA we used an Immulite* free and total PSA assay. Prostatic volume was determined with transrectal ultrasonography. Prostatic volume in BPH and prostate cancer patients was divided into 10 ml. groups, and mean ratio of free-to-total PSA was calculated for each volume group and both diseases. For statistical analysis Mann-Whitney U and Kruskal-Wallis tests were performed in addition to calculation of sensitivity and specificity, and receiver operator curves for prostates 60 ml. or less and greater than 60 ml.

Results

For BPH patients the mean ratio of free-to-total PSA was 14.64 to 25.14% without a close relation to prostatic volume. In prostate cancer patients a proportional increase from 8.45 to 19.37% in the ratio of free-to-total PSA with volume was found. Mann-Whitney U analysis revealed significant differences in prostate cancer versus BPH only in patients with prostates of 60 ml. or smaller (p = 0.0008 to 0.029). No significant differences were seen when prostate cancer and BPH patients with prostates larger than 60 ml. were compared (p = 0.082 to 0.868). Kruskal-Wallis test confirmed independence of the ratio of free-to-total PSA from prostatic volume in BPH patients (p = 0.285) but dependence in prostate cancer patients (p <0.0001). Sensitivity was higher in patients with prostates 60 ml. or smaller (86.72%) than in patients with prostates larger than 60 ml. (66%), and specificity was lower at 45.78 and 56.16%, respectively.

Conclusions

We have shown that the ratio of free-to-total PSA is influenced by prostatic volume in patients with prostate cancer. The ratio of free-to-total PSA provides useful information for differentiate BPH from prostate cancer in patients with small prostates but it is less useful in patients with larger prostates, probably because of the larger proportion of benign hypertrophic tissue.     

SERUM FREE PROSTATE SPECIFIC ANTIGEN AND PROSTATE SPECIFIC ANTIGEN DENSITY MEASUREMENTS FOR PREDICTING CANCER IN MEN WITH PRIOR NEGATIVE PROSTATIC BIOPSIES

Purpose

We examined the usefulness of measurements of free prostate specific antigen (PSA) and PSA density for predicting prostate cancer in men who had had a prior negative biopsy, a serum PSA level of 4.1 to 10.0 ng./ml. and benign findings on prostate examination.

Materials and Methods

We measured percent free serum PSA and PSA density in 163 male volunteers age 50 years or older who were advised to have repeat prostatic biopsies for a serum PSA level of 4.1 to 10.0 ng./ml.

Results

Of 99 men who had repeat biopsies 20 (20%) had prostate cancer detected. Prostate cancer was significantly associated with lower free PSA level and higher PSA density, with overlap in 83% of the cases. The use of percent free PSA cutoffs of 28 and 30% would have detected 90 and 95% of cancers, respectively, and avoided 13 and 12% of the biopsies, respectively. PSA density cutoffs of 0.10 and 0.08 would have detected 90 and 95% of cancers, respectively, and avoided 31 and 12% of biopsies, respectively.

Conclusions

Free PSA and PSA density predict prostate cancer in men who have had prior negative prostatic biopsies, serum PSA levels of 4.1 to 10.0 ng./ml. and a benign prostate examination. Both parameters may be used to avoid unnecessary biopsies with an acceptable decrease in sensitivity. Further studies are needed to determine cutoffs to be used in clinical practice.     

INFLUENCE OF FINASTERIDE ON FREE AND TOTAL SERUM PROSTATE SPECIFIC ANTIGEN LEVELS IN MEN WITH BENIGN PROSTATIC HYPERPLASIA

Purpose

Finasteride therapy for benign prostatic hyperplasia (BPH) results in a marked lowering of serum prostate specific antigen (PSA) levels. However, little is known about the effect of finasteride on unbound or free serum levels of PSA. Such information would be important since percent free PSA may substantially improve the cancer specificity of PSA testing. Thus, we prospectively studied the effect of finasteride therapy on total and free serum PSA levels.

Materials and Methods

In a randomized, placebo controlled, double-blind trial 40 men with histologically confirmed BPH (age range 52 to 78 years) were treated with either 5 mg. finasteride daily (26 patients) for 9 months or placebo (14) for 6 months. Prostate volume was assessed by transrectal ultrasound. Serum levels of free and total PSA were measured from archived serum samples stored at −70C at baseline and for as long as 9 months of treatment.

Results

In the finasteride group mean total PSA levels declined from 3.0 ng./ml. at baseline to 1.5 ng./ml. after 6 months of treatment (50% decrease, p < 0.01). In the placebo group, with similar baseline levels, no significant change was observed. PSA density declined significantly in finasteride treated men (p <0.01) but not in men receiving placebo. The mean percent free PSA (13 to 17% at baseline) was not altered significantly by finasteride or placebo.

Conclusions

Total PSA serum levels decreased by an average of 50% during finasteride therapy but percent free PSA did not change significantly. This information is potentially useful in the interpretation of PSA data used for early detection of prostate cancer in men receiving finasteride. However, further studies are required to demonstrate the use of percent free PSA to detect the development of cancer.     

STABILITY OF SERUM TOTAL AND FREE PROSTATE SPECIFIC ANTIGEN UNDER VARYING STORAGE INTERVALS AND TEMPERATURES

Purpose

Measurement of total serum prostate specific antigen (PSA) is widely used as an aid to early detection of prostate cancer. Measurement of the ratio of free-to-total PSA (percentage of free PSA) may help increase specificity of PSA testing. We prospectively studied the effects of varying the storage temperature and interval on total and free PSA levels.

Materials and Methods

We measured the baseline total and free serum PSA levels in 36 volunteers (mean age 66 years) and then retested aliquots of these serum samples after varying storage intervals (24 hours, 2 weeks and 9 months) at 3 different temperatures (4C, −20C and −70C). Volunteers represented a spectrum of prostatic conditions (PSA levels 2.0 to 4.0 ng./ml., PSA levels greater than 4.0 ng./ml. without cancer and PSA levels greater than 2.0 ng./ml. with prostate cancer). We used repeated measures analysis of variance to test for changes in total and free PSA levels as a function of time and temperature. We also evaluated the impact of storage at different temperatures and times on the percentage of free PSA.

Results

Across groups total and free serum PSA decreased from the baseline level differentially as a function of longer storage interval and higher temperature (p <0.05). No significant difference was found for change in total PSA at 24 hours, 2 weeks or 9 months for storage temperatures of −20C compared with −70C. A significant change from baseline level was found for free PSA when stored in −20C compared with −70C for 2 weeks but the magnitude of the change was modest.

Conclusions

For storage intervals up to 9 months total PSA is more stable than free PSA under temperature conditions ranging from 4C to −70C. This differential stability has important implications for the clinical evaluation of percentage of free PSA to distinguish between benign and malignant diseases of the prostate.     

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.     

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.     

THE USE OF PERCENT FREE PROSTATE SPECIFIC ANTIGEN FOR STAGING CLINICALLY LOCALIZED PROSTATE CANCER

Purpose

The free-to-total serum prostate specific antigen (PSA) ratio (percent free PSA) has been demonstrated to have clinical use for early detection of men with prostate cancer with total PSA levels between 4.0 and 10.0 ng./ml. Several studies evaluating the usefulness of percent free PSA for the staging of clinically localized prostate cancer have provided conflicting results. We further investigate the usefulness of percent free PSA for staging of clinically localized prostate cancer.

Materials and Methods

In 263 men with clinically localized prostate cancer who underwent radical prostatectomy total PSA and free PSA were measured preoperatively. Pathological stages were classified as organ confined in 134 cases, capsular penetration in 92, seminal vesicle involvement in 7, involvement of the surgical margins in 20 and lymph node involvement in 10.

Results

Percent free PSA was significantly different between men with organ confined versus nonorgan confined tumors (p <0.0001) and between those with favorable versus unfavorable pathology (p <0.0001). A cutoff of 12% free PSA provided a 72% positive predictive value and 52% negative predictive value for favorable pathology. A cutoff of 15% free PSA provided a 76% and 53% positive and negative predictive value, respectively, for organ confined disease.

Conclusions

These data demonstrate that the use of percent free PSA may be of additional value for the staging of clinically localized prostate cancer. The recommendations for cutoff levels of percent free PSA for detection and staging of localized prostate cancer are preliminary and can only be given for this particular assay. A large multicenter trial, controlling for age, stage and grade distribution, as well as for a uniform pathological evaluation and comparable total and free PSA assays, is required to elucidate this issue further.     

THE VALUE OF THE RATIO OF FREE-TO-TOTAL PROSTATE SPECIFIC ANTIGEN FOR STAGING PURPOSES IN PREVIOUSLY UNTREATED PROSTATE CANCER

Purpose

We analyzed the use of the ratio of free-to-total prostate specific antigen (PSA), also termed percentage of the free PSA, for predicting tumor stage, volume and grade in patients with clinically localized prostate cancer.

Materials and Methods

A total of 515 consecutive patients underwent further prostate evaluation due to elevated PSA (greater than 4.0 ng./ml.) or abnormal digital rectal examination. Prostate cancer was diagnosed in 307 patients (59.6%), including 170 (55.4%) who underwent radical retropubic prostatectomy. Data on pathological stage, Gleason grade, and total and Gleason grade 4 cancer volume were available in all patients. In the remaining 208 men (40.4%) benign prostate hyperplasia was diagnosed. Total and free PSA was measured in preoperative serum.

Results

Total PSA was significantly higher (p <0.0001) in the 71 men with stage pT3 tumors than in the 91 with pT2 disease. Eight patients had stage pT4 tumors. Cancer volume correlated well with advancing pathological stage (p <0.0001) and total PSA (p <0.0001). The free-to-total PSA ratio was not significantly different (p = 0.93) in stages pT2 and pT3 tumors, and it did not correlate with total (p = 0.71) or pure Gleason grade 4 (p = 0.94) cancer volume. However, the ratio of free-to-total PSA tended to decrease (p = 0.07) in tumors of increasing Gleason grade.

Conclusions

The ratio of free-to-total PSA does not help in the preoperative prediction of final tumor stage and volume. However, disease grading may alter the free-to-total PSA ratio.     

CHARACTERISTICS OF SCREENING DETECTED PROSTATE CANCER IN MEN 50 TO 66 YEARS OLD WITH 3 TO 4 NG./ML. PROSTATE SPECIFIC ANTIGEN

Purpose

We defined the yield and nature of prostate cancer in the setting of population based, randomized prostate specific antigen (PSA) guided screening in men with PSA levels between 3 and 4 ng./ml. who were 50 to 65 years old at the time of randomization.

Materials and Methods

Sextant biopsies were performed in 243 men with PSA of 3 to 4 ng./ml. Therapy decisions were based on core cancer length, histological grade and life expectancy.

Results

Of the men 32 (13.2%) had prostate cancer constituting 23% of all of the 137 prostate cancers to date detected in the first round of our screening study. Age and PSA were similar in men with and without prostate cancer. Men with prostate cancer had significantly lower free PSA and free-to-total PSA ratio, and higher PSA density. Cancer was clinical stage T1c in 27 cases and stage T2 in 5. Hypoechoic areas were noted at transrectal ultrasound in 10 cases. Digital rectal examination and transrectal ultrasound were normal in 21 cases (66%). To date 14 patients have undergone prostatectomy. Surgical specimens showed a mean tumor volume of 1.8 cc (range 0.6 to 4.4) and significant amounts of high grade tumor were present in only 3 cases. Margins were positive in 5 cases, and pathological stage was pT2 in 8 cases and pT3 in 6.

Conclusions

By lowering the PSA cutoff from 4 to 3 ng./ml. an increase in cancer detection by 30% was achieved. While the addition of free-to-total ratio and PSA density may reduce the number of biopsies by about 15% with sensitivity maintained at 90%, systematic sextant biopsies were necessary in most of these men as 66% of the tumors were negative on transrectal ultrasound and digital rectal examination. The majority of these cancers were clinically significant and suitable for curative treatment. If therapy decisions are based on the pathological findings of the biopsies, the risk of treating insignificant cancers seems low.     

TREATMENT OF EARLY RECURRENT PROSTATE CANCER WITH 1,25-DIHYDROXYVITAMIN D3 (CALCITRIOL)

Purpose

Substantial experimental and epidemiological data indicate that 1,25-dihydroxy-vitamin D3 (calcitriol) has potent antiproliferative effects on human prostate cancer cells. We performed an open label, nonrandomized pilot trial to determine whether calcitriol therapy is safe and efficacious for early recurrent prostate cancer. Our hypothesis was that calcitriol therapy slows the rate of rise of prostate specific antigen (PSA) compared with the pretreatment rate.

Materials and Methods

After primary treatment with radiation or surgery recurrence was indicated by rising serum PSA levels documented on at least 3 occasions. Seven subjects completed 6 to 15 months of calcitriol therapy, starting with 0.5 micro g. calcitriol daily and slowly increasing to a maximum dose of 2.5 micro g. daily depending on individual calciuric and calcemic responses. Each subject served as his own control, comparing the rate of PSA rise before and after calcitriol treatment.

Results

As determined by multiple regression analysis, the rate of PSA rise during versus before calcitriol therapy significantly decreased in 6 of 7 patients, while in the remaining man a deceleration in the rate of PSA rise did not reach statistical significance. Overall the decreased rate of PSA rise was statistically significant (p = 0.02 Wilcoxon signed rank test). Dose dependent hypercalciuria limited the maximal calcitriol therapy given (range 1.5 to 2.5 micro g. daily).

Conclusions

This pilot study provides preliminary evidence that calcitriol effectively slows the rate of PSA rise in select cases, although dose dependent calciuric side effects limit its clinical usefulness. The development of calcitriol analogues with decreased calcemic side effects is promising, since such analogues may be even more effective for treating prostate cancer.     

PROSTATE SPECIFIC ANTIGEN ADJUSTED FOR THE TRANSITION ZONE VOLUME AS AN INDICATOR OF PROSTATE CANCER

Purpose

We compared prostate specific antigen (PSA) adjusted for the transition zone volume with PSA and PSA density with regard to value in diagnosing prostate cancer in men with intermediate PSA levels of 4.1 to 10.0 ng./ml. in a community based urology practice.

Materials and Methods

Between October 1994 and May 1996, PSA transition zone was obtained from 92 of 94 men who underwent systematic sextant biopsies and had a PSA value between 4.1 and 10.0 ng./ml. PSA transition zone, calculated by dividing the PSA value by the volume of the transition zone of the prostate, was compared with PSA and PSA density via the receiver operating characteristic (ROC) curves.

Results

Of the 92 men 12 (13.0%) had prostate cancer. ROC curve analysis demonstrated that PSA transition zone and PSA density predicted the biopsy outcome significantly better than PSA (p <0.05 and p <0.01, respectively). In a subset of 59 men with normal digital rectal examination PSA transition zone predicted the biopsy outcome better than PSA density, although without significant difference. With a cutoff value of 0.3 PSA transition zone had a sensitivity of 75% and a specificity of 54%.

Conclusions

PSA transition zone is more specific than PSA in distinguishing benign from malignant disease in men with intermediate PSA levels of 4.1 to 10.0 ng./ml., especially in those with normal digital rectal examination. Further study is necessary to discuss whether PSA transition zone is superior to PSA density.     

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.     

Does normalizing PSA after successful treatment of chronic prostatitis with high PSA value exclude prostatic biopsy?

Objective

Evaluate male patients with diagnosed chronic prostatitis, elevated serum prostate-specific antigen (PSA) to find out whether medical treatment with antibiotics and anti-inflammatory drugs can lower serum PSA, and consequently decrease the prostate cancer detection rate in patients with post-treatment PSA<4 ng/mL.

Materials and methods

This prospective study evaluated 142 male patients aged 40-73 years whose presented with elevated serum PSA>4 ng/mL and were consequently diagnosed with chronic prostatitis as expressed prostatic excretions examination revealed more than 10 white blood cells per high power field. The Patients underwent treatment with antibiotics and nonsteroidal anti-inflammatory agents for 6-weeks. Subsequently, all patients are Followed-up by serum PSA and performed transrectal ultrasonography-guided prostate biopsy within 2 months of treatment.

Results

Mean patient age was (54.4±13.5) years. The mean PSA pretreatment was (8.11±3.7) ng/mL and after treatment, the mean PSA denoted a significant decrease to (4.7±3.5) ng/mL (P=0.002). The percent of changes in mean PSA was 41.9%. Prostatic biopsy after treatment showed that, cancer prostate in 31 patients (21.8%), chronic prostatitis in 71 patients (50.7%), chronic prostatitis plus benign prostatic hyperplasia (BPH) in 31 (21.8%) and BPH in 9 patients (6.3%) With regard to PSA values, cancer prostate patients were 3/25 (12%) if PSA<2.5 ng/mL, 6/47 (12.7%) if 4.0>PSA≥2.5 and 21/70 (30%) if PSA≥4.0. The numbers of cancer prostate detected patients were 30 (21.1%).

Conclusions

Chronic prostatitis is one of the causes that elevate serum PSA levels. Treatment of chronic prostatitis with elevated PSA by antibiotics and anti-inflammatory agents can decrease the elevated PSA to the normal levels. Nevertheless, the opportunities of potential prostate cancer still exist in patients with a decreased PSA level even also if PSA<2.5 ng/mL.     

CRYOSURGICAL ABLATION OF PROSTATE CANCER: PATTERNS OF CANCER RECURRENCE

Purpose

We determined the rate of biochemical and biopsy failure in relation to the prostate specific antigen (PSA) nadir, the effect of neoadjuvant androgen blockade and the pattern of residual tumor after cryosurgical ablation of prostate cancer.

Materials and Methods

From July 1993 to April 1996, 134 patients underwent 147 cryosurgical ablation procedures. Of those patients, 110 had adequate followup and did not receive post-treatment androgen deprivation. Followup included PSA determination at 3, 6 and 12 months, and every 6 months thereafter. Biopsies were performed at 6 months or with biochemical failure defined as PSA nadir 0.5 ng./ml. or greater or subsequent biochemical failure (PSA increase 0.2 ng./ml. or greater). Biochemical and biopsy failures were correlated with PSA nadir values following cryosurgery (less than 0.1 ng./ml., 0.1 to 0.4 and or greater 0.5). A total of 68 patients had careful ultrasound guided mapping biopsy preoperatively and postoperatively to define the sites of disease. The likelihood of residual disease was correlated with the initial site(s) of the cancer in an attempt to identify if areas of the prostate and/or seminal vesicles were more likely to be sites of treatment failure.

Results

At a mean followup of 17.6 months biochemical failure (subsequent rise in PSA 0.2 ng./ml. or greater) was lowest in those who achieved PSA nadirs less than 0.1 ng./ml. (21%) but it was noted in 48% of patients with nadirs between 0.1 and 0.4 ng./ml. Those patients with PSA nadirs 0.5 or greater had either immediate local failure (46%), subsequent local or biochemical failures (43%) or extremely high PSA nadirs (greater than 30 ng./ml.) necessitating hormonal therapy (11%). Biopsy failure was lowest in those with nadirs less than 0.1 ng./ml. (7%) and those with nadirs 0.1 to 0.4 ng./ml. (22%). In contrast, 60% of the patients with nadir values 0.5 ng./ml. or greater had biopsy failure. Biochemical and biopsy failure tended to occur within the first 18 months after treatment. Neoadjuvant androgen blockade appeared to reduce subsequent biochemical failure in patients with stages T1 and T2 cancers (11% versus 50% in those without androgen deprivation) but not in those with T3 and T4 cancers. Recurrence was more common in cancers at the apex (9.5%) and seminal vesicles (44%), in contrast to those located in the mid gland (4%) and base (0%).

Conclusions

A PSA nadir of 0.4 ng./ml. or less should be achieved following cryotherapy. Higher values are associated with a significant risk of continued PSA elevation and a high likelihood of residual disease detected on prostatic biopsy. Local failure tends to occur at the apex and seminal vesicles. Neoadjuvant androgen blockade reduces the risk of biochemical failure in patients with stages T1 and T2 cancers.     

Effect of Digital Rectal Examination and Needle Biopsy on Serum Total and Percentage of Free Prostate Specific Antigen Levels

Purpose

We determined the effect of digital rectal examination and prostatic biopsy on serum total and free prostate specific antigen (PSA) concentrations in men undergoing screening for prostate cancer.

Materials and Methods

In 93 men recruited from our PSA screening program we measured the serum concentrations of total and free PSA on 3 occasions during a 30-day interval before performing digital rectal examination. Total and free PSA measurements were repeated 1 and 24 hours after the rectal examination. Serum total and free PSA also was measured immediately before, and 1 hour, 24 hours and 1 week after prostatic biopsy in 30 men.

Results

Biological variation for total and free PSA was 14.7 and 14.0%, respectively. At 1 hour after rectal examination total and free PSA increased by more than the biological variation in 31 and 48% of the men, respectively. Increases were significantly greater in men whose initial PSA concentrations were less than 4.0 ng./ml. There was a dramatic increase in total and percentage of free PSA in all men 1 hour after prostatic biopsy. Increases in percentage of free PSA were greater in men whose biopsies revealed cancer. Total PSA remained elevated for at least 1 week in most men, while percentage of free PSA returned to within or less than the biological variation of the baseline level in 90% of the men by 24 hours.

Conclusions

Digital rectal examination causes a modest increase in total and percentage of free PSA. Prostate needle biopsy causes more dramatic increases in both forms of PSA. Free PSA is preferentially released into the serum after prostatic manipulation and appears to be cleared more rapidly than complexed PSA. The differential return of the different PSA forms to baseline levels after biopsy could affect the use of measurements of the percentage of free PSA in clinical practice.     

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.     

INDUCTION OF PROSTATE APOPTOSIS BY DOXAZOSIN IN BENIGN PROSTATIC HYPERPLASIA

Purpose

The molecular mechanisms underlying the therapeutic effect of the alpha 1 blocker, doxazosin, on benign prostatic hyperplasia (BPH) are poorly understood. We evaluated the effect of doxazosin on cell proliferation and apoptosis in the prostatic glandular epithelium and stroma of patients with BPH.

Materials and Methods

We examined proliferative and apoptotic activities in prostate specimens of 22 men a mean of 65 years old with BPH before and after doxazosin treatment within the normal therapeutic range. Proliferative and apoptotic indexes were determined using Ki-67 nuclear antigen staining and the terminal transferase end labeling assay, respectively. The smooth muscle cell content in prostatic specimens was identified by smooth muscle alpha-actin, and desmin immunoreactivity and apoptotic indexes were correlated with prostatic stromal tissue regression and improvement in BPH symptoms.

Results

In response to doxazosin treatment there were no significant changes in the kinetics of cell proliferation in the prostatic epithelial or stromal cell population. Mean pretreatment baseline apoptosis was 1.9 and 1.0% for the epithelial and stromal prostate components, respectively. Mean apoptotic indexes significantly increased after 3 months of doxazosin treatment in the glandular epithelial (6%) and smooth muscle cells (15%). By 12 months after treatment epithelial apoptosis had decreased to constitutive levels, while the apoptotic index of prostatic stroma cells remained high. Doxazosin induced smooth muscle cell apoptosis correlated with prostatic stromal degeneration, decreased alpha-smooth muscle actin expression and improved BPH symptoms.

Conclusions

These findings implicate the induction of prostate apoptosis by doxazosin as a potential molecular mechanism underlying the acute and chronic therapeutic responses of BPH to alpha 1 blockade.     

High serum prostate-specific antigen levels in the absence of prostate cancer in Middle-Eastern men: the clinician's dilemma

OBJECTIVE: To investigate the common causes of total serum prostate-specific antigen (PSA) values of> 10 ng/mL in an Arab population, as in the USA and Europe the risk of prostate cancer is considered high in men with such PSA levels. PATIENTS AND METHODS: Serum total PSA was measured in men presenting to our hospital as part of the investigation for prostate cancer screening and/or in elderly men with prostatism. Men with a serum PSA level of> 10 ng/mL were further investigated by transrectal ultrasonography (TRUS) of the prostate and biopsy of suspicious lesions for histological diagnosis. In addition, the percentage of free PSA, PSA velocity and PSA density were determined. All the patients included in this study were men of Arab origin residing in Kuwait. RESULTS: In all, 1700 men (mean age 55.6 years, range 35-94) were assessed; of these, 161 had a serum PSA of> 10 ng/mL, attributable to benign prostatic hyperplasia (BPH) in 110 (68%), BPH with histological features of prostatitis in 33 (21%) and prostate cancer in 18 (11%). TRUS of the prostate in 143 of the 161 men with either BPH or BPH with prostatitis showed varying grades of intraprostatic calcifications in 22 (15%). Both PSA density and percentage free PSA did not contribute to determining the causes of total PSA levels of> 10 ng/mL. There was a progressive decline in PSA in all patients with BPH and prostatitis, except one who at re-biopsy had prostate cancer (T1N0M0, G1). CONCLUSION: Total PSA values of> 10 ng/mL in Arab men may be a result of BPH, BPH with prostatitis or prostate cancer, in that order. A gradual decline in total PSA (decreased PSA velocity) with time to < 4 ng/mL often confirms the diagnosis of BPH with prostatitis. The percentage of free PSA and PSA density may not be helpful in diagnosing prostate cancer with certainty in these patients. Compared with Caucasians in the USA and Europe, BPH and BPH with prostatitis appear to be more frequent causes of serum PSA levels of> 10 ng/mL in Arab men.     

PRELIMINARY OUTCOMES FOLLOWING CRYOSURGICAL ABLATION OF THE PROSTATE IN PATIENTS WITH CLINICALLY LOCALIZED PROSTATE CARCINOMA

Purpose

Cryosurgical ablation of the prostate is a novel therapeutic modality that induces cell lysis in the prostate by direct application of low temperatures. We have been conducting an ongoing prospective pilot study of the use of cryosurgical prostate ablation in treating patients with nonmetastatic prostate adenocarcinoma since January 1993. Results in 145 consecutive patients with mean 36 months and minimum 12 months of followup are presented.

Materials and Methods

Accrual was open to patients with clinical stages T1a to T3c prostate adenocarcinoma. Pelvic lymph node dissections were recommended but not required for patients with prostate specific antigen (PSA) greater than 15 ng./ml. before study entry. PSA changes, random prostate biopsy findings and morbidities after cryosurgical prostate ablation were recorded for each patient.

Results

Overall actuarial rates at 42 months for maintaining PSA less than 0.3 and less than 1.0 were 59% and 66%, respectively. The overall actuarial progression-free rate at 60 months was 56%. Among 160 biopsies performed 16% showed some evidence of residual carcinoma. Overall crude rates of maintaining either a negative biopsy or PSA less than 0.3 at 6 and 24 months after cryosurgical prostate ablation were 87% and 73%, respectively. Significantly higher morbidities were seen in previously radiated patients undergoing cryosurgical prostate ablation compared to those with no prior radiation. Among nonradiated patients 85% experienced no significant morbidity after cryosurgical prostate ablation.

Conclusions

Although preliminary, short-term outcomes after cryosurgical prostate ablation appear to be comparable to identical outcomes reported for external beam radiotherapy. Based on these results cryosurgical prostate ablation appears to be an effective therapeutic alternative for treating patients with localized prostate adenocarcinoma.