The Free-To-Total Prostate Specific Antigen Ratio Improves the Specificity of Prostate Specific Antigen in Screening for Prostate Cancer in the General Population

Purpose

The ratio between free and total prostate specific antigen (PSA) in serum improves the specificity of total serum PSA for the detection of prostate carcinoma in select populations. The value of the free-to-total PSA ratio for a PSA of 4.0 to 10.0 ng./ml. was analyzed in a screening population.

Materials and Methods

From 4,800 participants 55 to 76 years old 977 biopsies were obtained because of an abnormal digital rectal examination, suspicious transrectal ultrasonography and total serum PSA 4.0 ng./ml. or more. Of 191 patients with prostate carcinoma detected 101 had a serum PSA of 4.0 to 10.0 ng./ml. and 54 of them underwent radical prostatectomy. A free-to-total PSA ratio of 0.20, age specific PSA reference ranges and a PSA density of 0.12 ng./ml./cc were evaluated for the ability to increase the specificity of total serum PSA in predicting positive prostate biopsy results.

Results

Receiver operating characteristics curves for the free-to-total PSA ratio showed a significant increase in specificity compared to PSA. Retrospective application of age specific PSA reference ranges, the free-to-total PSA ratio and the PSA density decreased the number of biopsies significantly by up to 40% in our study, with a decrease in cancer detection rate of 12%. When used in combination with digital rectal examination, the pathological stage of undetected carcinomas appeared favorable.

Conclusions

The free-to-total PSA ratio may be used to decrease biopsies in patients with an intermediate PSA of 4.0 to 10.0 ng./ml.     

Prevalence and Predictors of a Positive Repeat Transrectal Ultrasound Guided Needle Biopsy of the Prostate

Purpose

We determined the prevalence of and risk factors for carcinoma in patients with 1 previously negative prostate biopsy.

Materials and Methods

Transrectal ultrasound guided prostate needle biopsies were repeated in 130 men. Risk factors analyzed included age, pathological result of initial biopsy, inter-biopsy interval, prostate specific antigen (PSA), PSA density, PSA velocity, digital rectal examination, abnormal transrectal ultrasound and family history of prostate cancer.

Results

A total of 39 patients (30%) had positive biopsies for cancer. Univariate analysis revealed that PSA more than 20 ng./ml. and abnormal transrectal ultrasound were more frequent in men with positive second biopsies. Using multivariate logistic regression analysis only PSA more than 20 ng./ml. was a significant risk factor (adjusted odds ratio 4.48, 95% confidence interval 1.02 to 20.1). We determined the incidence of carcinoma in patients who represent the lowest risk group as defined by PSA less than 10 ng./ml., PSA density less than 0.15 mg./ml./cm.³, PSA velocity less than 0.75, ng./ml. per year, no prostatic intraepithelial neoplasia plus negative transrectal ultrasound, digital rectal examination and family history. Of 21 patients who fit this cohort 5 (23.8%) had carcinoma on repeat biopsy.

Conclusions

A significant false-negative rate for initial transrectal ultrasound guided prostate biopsies exists. Baseline risk in lowest risk patients is sufficiently high such that one cannot define a subset of patients for whom repeat biopsy is unnecessary. We recommend repeat biopsy in all patients who meet the criteria for a transrectal ultrasound guided biopsy and in whom the initial biopsy is negative.     

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.     

Significance of Serum Free Prostate Specific Antigen in the Screening of Prostate Cancer

Purpose

The significance of serum free prostate specific antigen (PSA) in the screening of prostate cancer was examined.

Materials and Methods

A prospective clinical trial was conducted on 701 male volunteers 50 years old or older. Serum free PSA was determined and biopsies were performed if PSA was greater than 4 ng./ml. or if digital rectal examination was suspicious for cancer.

Results

Of the men 187 (27 percent) had a PSA of greater than 4 ng./ml. (11 percent) and/or a suspicious digital rectal examination (19 percent). Of 116 biopsies performed in the 701 men cancer was detected in 13 (1.9 percent). PSA detected more tumors (12 of 13, 92 percent) than digital rectal examination (9, 69 percent). Receiver operating characteristic analysis showed that the optimal free PSA-to-PSA ratio (free PSA ratio) was 12 percent. The positive predictive value for cancer according to PSA with free PSA ratio (50 percent, 10 cancers in 20 biopsies) was significantly greater (p = 0.0473) than that according to PSA alone (24 percent, 12 cancers in 50 biopsies), which indicated that 30 of 50 biopsies were avoided with only 2 cancers missed when PSA and free PSA were used for biopsy indication.

Conclusions

Free PSA determination might eliminate unnecessary biopsies in men with a PSA of more than 4 ng./ml. with minimal missed cancers.     

Prostate Specific Antigen Density Versus Prostate Specific Antigen Slope as Predictors of Prostate Cancer in Men with Initially Negative Prostatic Biopsies

Purpose

We determined if prostate specific antigen (PSA) density and PSA slope alone or in combination could be used to predict which men with persistently elevated serum PSA and prior negative prostate biopsies will have prostate cancer on repeat evaluation.

Materials and Methods

In our PSA-1 data base we identified 327 men 50 years old or older with an initially negative prostate biopsy who had persistent PSA elevation, and compared those who did and did not have prostate cancer on subsequent serial prostatic biopsy.

Results

Of 70 men with a PSA density of 0.15 or more and PSA slope of 0.75 ng./ml. or more annually compared to 83 with a PSA density of less than 0.15 and PSA slope of less than 0.75 ng./ml. annually 32 (46 percent) and only 11 (13 percent), respectively, had prostate cancer on subsequent prostate biopsies (p less than 0.0001). In a hierarchical logistic regression analysis PSA density and PSA slope were predictive of prostate cancer on subsequent biopsy (p = 0.001 and 0.03, respectively). PSA density of 0.15 or more alone or PSA slope of 0.75 ng./ml. or more annually alone as the indicator for repeat biopsy would have missed 35 and 40 percent of cancers, respectively.

Conclusions

In men with persistently elevated serum PSA after an initially negative prostate biopsy, PSA density and PSA slope alone or in combination provide useful predictive information about the results of repeat prostate biopsies. However, these parameters are not sufficiently sensitive to identify all patients with detectable prostate cancer.     

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.     

Cancer Diagnosis with Prostate Specific Antigen Greater than 10 ng./ml. and Negative Peripheral Zone Prostate Biopsy

Purpose

We assessed the results of additional diagnostic procedures in men with prostate specific antigen (PSA) more than 10 ng./ml. and a peripheral zone prostate biopsy negative for cancer.

Materials and Methods

A total of 68 men with PSA more than 10 ng./ml. and a peripheral zone biopsy negative for cancer was investigated with 1 or more peripheral zone biopsies (17), prostatectomy (18), or 1 or more peripheral zone biopsies and needle biopsy of the transition zone or prostatectomy (33).

Results

Cancer was detected in 20 of 68 patients (29 percent) with 1 or more additional diagnostic procedures. Of 51 patients whose transition zone was biopsied or who underwent prostatectomy 16 had cancer, and in 8 the malignancy appeared to be isolated to the transition zone. Mean PSA density and proportion of patients with PSA density more 0.15 were significantly greater and mean prostate volume was significantly less in the 20 patients with compared to 31 without identifiable cancer.

Conclusions

At least 30 percent of men with PSA more than 10 ng./ml. and a negative peripheral zone biopsy have prostate cancer. In approximately 50 percent of cases the cancer appears to reside in the transition zone, and transition zone biopsy or prostatectomy is required for diagnosis.     

Prostatic Intraepithelial Neoplasia: Influence of Clinical and Pathological Data on the Detection of Prostate Cancer

Purpose

We attempted to characterize patients diagnosed with prostatic intraepithelial neoplasia without concurrent cancer on biopsy who had prostate cancer on subsequent biopsy.

Materials and Methods

The records of 93 patients with low and high grade prostatic intraepithelial neoplasia without concurrent cancer on initial biopsy were analyzed. The relationships among prostatic intraepithelial neoplasia grades, patient age, digital rectal examination, serum prostate specific antigen (PSA), transrectal ultrasound appearance and final pathological results were investigated.

Results

Subsequent carcinoma was found on repeat biopsy in 13.3 percent of patients with low grade and 47.9 percent with high grade prostatic intraepithelial neoplasia (p less than 0.001). In the former group digital rectal examination, patient age, serum PSA and transrectal ultrasound were not predictive of cancer. Transrectal ultrasound appearance, digital rectal examination and serum PSA were statistically different between high grade prostatic intraepithelial neoplasia with and without subsequent cancer (p less than 0.001, p = 0.008 and p = 0.016, respectively, univariate analysis). On multivariate analysis of patients with high grade prostatic intraepithelial neoplasia only digital rectal examination and PSA were predictive of subsequent carcinoma.

Conclusions

High grade prostatic intraepithelial neoplasia is a strong predictor of subsequent cancer, especially in men with abnormal digital rectal examination and elevated serum PSA. Patients with high grade prostatic intraepithelial neoplasia should undergo repeat biopsy to exclude cancer. Further investigations are needed to optimize the treatment of patients with low grade prostatic intraepithelial neoplasia.     

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.     

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.     

Pathological Characteristics and Prognosis of Nonpalpable and Palpable Prostate Cancers with a Hybritech Prostate Specific Antigen of 4 to 10 ng./ml

Purpose

We compared the surgical pathological findings and postoperative course of patients with palpable and nonpalpable prostate cancers.

Materials and Methods

All patients with untreated prostate specific antigen (PSA) 4 to 10 ng./ml. who underwent radical prostatectomy between December 1984 and December 1993 were reviewed to select 61 with clinical stage T1c (nonpalpable) and 209 with stages T2a to c (palpable) disease.

Results

Nonpalpable cancers were smaller (2.99 versus 4.42 cc for palpable tumors), had smaller volumes of Gleason grade 4 or 5 cancer (0.66 versus 1.32 cc, respectively) and were less likely to have positive surgical margins (13 versus 22 percent, respectively) or significant (1 cm. or more) capsular penetration (10 versus 26 percent, respectively). Nonpalpable and palpable cancers had similar rates of seminal vesicle invasion (3.3 versus 4.3 percent, respectively) and positive lymph nodes (1.6 versus 0 percent, respectively). More than 90 percent of patients with nonpalpable cancer were biochemically cancer-free postoperatively, and the remainder were alive with disease after a mean followup of 25.1 months, compared to 69 percent disease-free, 28 percent alive with disease and 2.5 percent dead of prostate cancer after a mean followup of 43.8 months among those with palpable disease.

Conclusions

We conclude that nonpalpable prostate cancers are pathologically more favorable than palpable prostate cancers with PSA 4 to 10 ng./ml. Our preliminary results also indicate that nonpalpable cancers are less likely to recur postoperatively than palpable cancers with a similar PSA range.     

Prostate cancer detection at low prostate specific antigen

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

Free-to-Total Prostate Specific Antigen Ratio as a Single Test for Detection of Significant Stage T1c Prostate Cancer

Purpose

We investigated whether impalpable, invisible (stage T1c) but significant prostate cancer can be detected better by determining the free-to-total prostate specific antigen (PSA) ratio of equivocal PSA serum levels.

Materials and Methods

The specificity of free-to-total PSA ratio using research monoclonal enzyme immunoassays was compared to that of PSA greater than 4.0 ng./ml. in 117 consecutive patients with PSA 3 to 15 ng./ml. (Hybritech Tandem-R assay) due to untreated benign prostatic hypertrophy or prostate cancer. Of the patients 77 percent underwent adenectomy or radical prostatectomy with thorough pathological evaluation of surgical specimens.

Results

Benign prostatic hypertrophy had a greater median free-to-total PSA ratio than stages T1c and T2 or greater prostate cancer (0.16 versus 0.09 and 0.11 ng./ml., p = 0.0001 and p = 0.0268, respectively). In stage T1c prostate cancer, areas under receiver operating characteristic curves were 0.58 and 0.84 for PSA and free-to-total PSA ratio, and free-to-total PSA ratio correlated with prostate volume (r = 0.49, p = 0.005) and Gleason score (r = -0.37, p = 0.036). Pathologically, 84 percent of stage T1c cancers were significant and comparable to stage T2 or greater cancers.

Conclusions

Free-to-total PSA ratio enhances the efficacy of PSA measurement by improving specificity for detecting impalpable, invisible but significant stage T1c prostate cancer.     

AGE SPECIFIC PROSTATE SPECIFIC ANTIGEN REFERENCE RANGES: POPULATION SPECIFIC

Purpose

We determined whether 60 to 79-year-old men with a negative digital rectal examination and a serum prostate specific antigen (PSA) within age specific PSA reference ranges could safely forgo prostate biopsy.

Materials and Methods

We reviewed the medical records of all 60 to 79-year-old men at the Brooklyn Veterans Administration Medical Center who had a PSA assay, digital rectal examination and subsequent prostate biopsy for an abnormal rectal examination and/or PSA greater than 4.0 ng./ml. from January 1991 through August 1995. We compared our results using the standard reference range of 0 to 4.0 ng./ml. with those obtained had we used any of 4 different age specific PSA reference ranges.

Results

We performed 1,280 prostate biopsies in 1,046 men with available PSA and digital rectal examination data. Using age specific PSA reference ranges 73 of 1,280 biopsies (5.7%) would have been avoided. Of those 73 avoided biopsies 15 (20.5%) had cancer that would have gone undetected and 9 of 15 (60%) undetected cancers had unfavorable histology. Results were not statistically significantly different among the 4 age specific PSA reference ranges. Regarding race, cancer detection rates were significantly higher for black compared with white men but there was no statistically significant difference for missed cancers or missed cancers with unfavorable histology.

Conclusions

In contrast to previous reports of unfavorable histological characteristics in only 5% of missed cancers using age specific PSA reference ranges, 60% of missed cancers in our patients exhibited unfavorable histology. We conclude that age specific PSA reference ranges did not safely eliminate the need for prostate biopsy in our study population. In 60 to 79-year-old men with a negative digital rectal examination we continue to use PSA greater than 4.0 ng./ml. as an indication for prostate biopsy.     

Can Free and Total Prostate Specific Antigen and Prostatic Volume Distinguish Between Men With Negative and Positive Systematic Ultrasound Guided Prostate Biopsies?

Purpose

We evaluated the role of free and total serum prostate specific antigen (PSA) and prostate volume in discriminating between men with negative and positive transrectal ultrasound guided biopsies.

Materials and Methods

A total of 104 consecutive men with a positive biopsy and at least 3 mm. of prostate cancer was compared to 110 consecutive men with a negative biopsy. Prostate volume was determined by transrectal ultrasound. Total PSA was determined by the Tosoh AIA-600† PSA assay and free PSA was measured by the PSA II Dianon‡ assay. We determined the free-to-total PSA ratio, free and total PSA densities, and the relationship of free PSA and free-to-total PSA ratio to prostate volume.

Results

Using a 23% cutoff value of free-to-total PSA, only 22.7% of biopsies were preventable in patients with a negative biopsy but 9.6% of the cancers were missed. At a total PSA of 4 to 10 ng./ml. 44.4% of the biopsy negative cases were correctly identified while missing 9.1% of the cancers if a 20% free PSA cutoff is used. For total PSA more than 10 ng./ml. an 18% free PSA cutoff properly identified 30.2% of the biopsy negative cases while missing 9.3% of the cancers. Percent free PSA is a better discriminant than prostate volume for total PSA more than 4 ng./ml. and the combination was not helpful. Free PSA density was identical in patients with negative and positive biopsies. There was no relationship between free PSA or free-to-total PSA ratio levels and prostate volume.

Conclusions

Use of a single discriminant criterion of free-to-total PSA ratio in the practical clinical setting of distinguishing negative and positive biopsies appears useful in patients with a total PSA of 4 to 10 ng./ml. Since free PSA is unrelated to prostate volume in biopsy negative and positive cases the physiological basis of free PSA is an enigma.     

Preoperative Prediction of Tumor Heterogeneity and Recurrence After Radical Prostatectomy for Localized Prostatic Carcinoma with Digital Rectal Examination, Prostate Specific Antigen and the Results of 6 Systematic Biopsies

Purpose

Digital rectal examination, preoperative serum prostate specific antigen (PSA) concentration and results of 6 ultrasound guided systematic sextant biopsies in 257 consecutive patients with clinical stages T2 and T1c prostatic carcinoma were evaluated for their use in predicting pathological stage and tumor recurrence.

Materials and Methods

Each of the 257 consecutive specimens was examined using the 3 mm. step section technique. Results of preoperative digital rectal examination, PSA and 6 systematic sextant biopsies were correlated with pathological stage, margin status and postoperative PSA during a mean followup of 2 years. Patients were considered to have disease progression based on an elevated PSA level by a supersensitive assay.

Results

Digital rectal examination could not predict pathological stage and tumor recurrence. Preoperative PSA concentration, number of positive biopsies and tumor grade in the biopsy specimens correlated well with pathological stage. The best predictor of tumor recurrence was the biopsy result. However, a precise prediction of outcome (87 percent probability of being PSA negative versus 0 percent) was possible only in a third of the patients if the biopsy results were used. Use of preoperative PSA concentration did not improve this probability.

Conclusions

Preoperative PSA concentration and/or biopsy results correlate significantly with pathological stage and margin status. Precise prediction of tumor recurrence is possible in only approximately a third of the patients with clinical stage T2 prostatic carcinoma.     

Sensitive Prostate Specific Antigen Measurements Identify Men With Long Disease-Free Intervals and Differentiate Aggressive from Indolent Cancer Recurrences within 2 Years After Radical Prostatectomy

Purpose

Commonly available prostate specific antigen (PSA) assays have detection limits of greater than 0.05 ng./ml., limiting their ability to identify residual or recurrent prostate cancer after radical prostatectomy or to provide prognostic information within the first several years after surgery. We investigated the ability of a sensitive PSA assay to identify residual prostate cancer and men at risk for early recurrence after radical prostatectomy.

Materials and Methods

We measured PSA in 1,037 serum samples obtained serially from 127 men after radical prostatectomy using the IMMULITE' third generation PSA assay.'Diagnostic Products Corp., Los Angeles, California.

Results

The IMMULITE PSA assay has an analytical sensitivity of less than 0.002 ng./ml. and a clinically useful decision threshold of 0.01 ng./ml. With this assay our patients were classified into 3 groups: 1) 50 with a postoperative baseline PSA of less than 0.01 ng./ml. that did not change during an average of 36 months postoperatively, 2) 66 with increasing PSA that exceeded 0.01 ng./ml. in all cases by 30 months postoperatively (20 with clinical cancer recurrences) and 3) 11 with slowly increasing PSA of greater than 0.01 but less than 0.02 ng./ml. at an average of 36 months postoperatively.

Conclusions

The IMMULITE PSA assay provides clinically useful information not previously available from PSA assays with conventional sensitivity, which is highly predictive of cancer activity in patients within 2 years after radical prostatectomy.     

Clinical Efficacy of Bone Alkaline Phosphatase and Prostate Specific Antigen in the Diagnosis of Bone Metastasis in Prostate Cancer

Purpose

We investigated the usefulness of bone alkaline phosphatase isoenzyme and prostate specific antigen (PSA) determined by radioimmunoassay to predict bone scan evidence of metastasis in newly diagnosed untreated and treated prostate cancer.

Materials and Methods

We analyzed bone alkaline phosphatase enzyme concentrations in 350 men, including 150 controls, 100 with benign prostatic hyperplasia and 100 with prostate cancer (52 with stage T1 to 4, M0 and 48 with stages T1 to 4, M1 to 4). We also analyzed bone alkaline phosphatase enzyme concentrations in 61 stages T1 to 4, M0 prostate cancer cases during followup after radical prostatectomy or hormonal therapy, and 17 had clinical progression (9 with local, 5 with lymph node and 3 with bone metastases). Simultaneously, we analyzed PSA concentrations.

Results

Average bone alkaline phophatase enzyme levels were 12, 11.1 and 10.0 ng./ml. in the control, benign prostatic hyperplasia and stage M0 prostate cancer groups, respectively (p not significant), and 83.2 ng./ml. in patients with stage M1 to 4 disease (p less than 0.001). Considering that to diagnose bone metastasis the cutoff for bone alkaline phosphatase enzyme and PSA is 30 ng./ml. and 100 ng./ml., respectively, clinical effectiveness was 93.7 percent and 81.8 percent, respectively. Finally, measurement of both substances at the same time increased clinical effectiveness to 97.9 percent. During followup a bone alkaline phosphatase enzyme level that becomes greater than 30 ng./ml. (0 percent in the local and lymphatic progression groups, and 100 percent in the bone metastasis group) indicates the need to perform a bone scan.

Conclusions

We recommend the clinical use of bone alkaline phosphatase enzyme determined by radioimmunoassay and PSA measurement for the diagnosis of bone metastases and progression of prostate cancer because of the good sensitivity and specificity.     

Extraprostatic Production of Prostate Specific Antigen is Under Hormonal Control

Purpose

Prostate specific antigen (PSA) is the most useful tumor marker in urology. It is produced primarily by the epithelial cells of the ducts and acini of the prostate gland. Extraprostatic production of PSA is provided mainly by the periurethral glands, leading to measurable urine but undetectable serum levels of PSA in women and in men following radical prostatectomy for pathologically localized disease.

Materials and Methods

We investigated the effect of continuous testosterone substitution (250 mg. every 4 weeks) on urinary PSA excretion in 20 patients who converted from the female to male gender. We compared the results to urine levels in 20 women who did not receive testosterone.

Results

Mean urinary PSA plus or minus standard deviation was 1.73 +/− 1.68 ng./ml. in controls and 12.03 +/− 10.47 ng./ml. in converted patients, a statistically significant difference (p <0.0001). Serum PSA did not differ between groups.

Conclusions

Our data demonstrate that extraprostatic PSA production is under androgen control.     

Pitfalls in Interpreting Prostate Specific Antigen Velocity

Purpose

The concept of prostate specific antigen (PSA) velocity as an improved marker for prostate cancer detection is intriguing. However, before this concept is applied to individual patients several confounding parameters must be addressed. We determined the variability of serum PSA levels in men without prostate cancer.

Materials and Methods

We reviewed data from a prostate cancer screening program, and determined inter-assay and individual variability of the serum PSA values for a 2-year followup period in 265 men clinically free of prostate cancer.

Results

Our average inter-assay coefficient of variation was 7.5 percent. Therefore, we considered only PSA changes exceeding plus/minus 15 percent as significant. Fluctuations in serum PSA occurred in 78 percent of the men during the observation period, and 12.5 percent had at least a single PSA increase exceeding 0.75 ng./ml. per year. Fluctuations were noted throughout the entire range of serum PSA levels but became progressively larger with an increasing mean PSA.

Conclusions

The inter-assay variability must be considered when interpreting PSA velocity. Individual fluctuations in serum PSA dictate an observation period of at least 2 years before PSA velocity is considered abnormal.