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.     

Radiotherapy for High Grade Clinically Localized Adenocarcinoma of the Prostate

Purpose

We defined the efficacy of radiotherapy for the treatment of high grade (Gleason scores 8 to 10) adenocarcinoma of the prostate.

Materials and Methods

A total of 50 patients underwent radiotherapy with curative intent for clinically localized prostate cancer with Gleason scores of 8 to 10 at 1 of 4 facilities affiliated with the University of California San Francisco. Patients were considered to have biochemical failure if they had a significant increase in prostate specific antigen (PSA) of 0.5 ng./ml. per year, an increase in PSA to greater than 1.0 ng./ml. or a positive biopsy.

Results

Among the 50 patients median PSA was 22.7 ng./ml. (range 1.3 to 93.4). Tumors were clinical stage T1 or T2 in 46 percent of the cases and stage T3 or T4 in 54 percent. The overall actuarial probability of freedom from biochemical failure at 4 years was 23 percent. In a multivariate analysis including all patients pretreatment PSA was the only predictor of PSA failure, with 64 percent free of progression if the pretreatment PSA was 10 ng./ml. or less compared to only 16 percent at 3 years if PSA was more than 10 ng./ml. (p = 0.01). In a multivariate analysis restricted to patients with PSA less than 20 ng./ml. 83 percent of those treated to more than 71 Gy. were free of progression compared to 0 percent for those treated to less than 71 Gy. (p = 0.03). In a multivariate analysis PSA 10 ng./ml. or less (related risk 11.4, p = 0.02), T stage 1 or 2 (relative risk 3.8, p = 0.05) and radiation dose more than 71 Gy. (relative risk 4.0, p = 0.06) were associated with a favorable outcome.

Conclusions

At 4 years the freedom from PSA failure following radiotherapy for high grade prostate cancer was comparable to previously reported surgical series. The high failure rate among patients with PSA greater than 20 ng./ml. suggests that these patients should be considered for investigational approaches. The apparent improvement in freedom from progression with the use of higher doses provides reason for optimism.     

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.     

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.     

Standard Versus Age-Specific Prostate Specific Antigen Reference Ranges Among Men With Clinically Localized Prostate Cancer: A Pathological Analysis

Purpose

Age-specific prostate specific antigen (PSA) reference ranges have been suggested to account for the age-dependent nature of the serum PSA concentration. It has been hypothesized that reference ranges of 0 to 2.5 ng./ml. serum PSA (40 to 49 years), 0 to 3.5 ng./ml. (50 to 59 years), 0 to 4.5 ng./ml. (60 to 69 years) and 0 to 6.5 ng./ml. (70 to 79 years) would detect fewer (potentially insignificant) prostate cancers in older men and more (potentially curable) cancers in younger men.

Materials and Methods

To investigate the pathological stage of tumors that would be affected by the use of age-specific PSA reference ranges, we reviewed the medical records for 4,597 men with clinically localized (stage T1c, T2 or T3a) prostate cancer, with an average age of 62 plus/minus 7 years (range 38 to 76), who underwent radical prostatectomy between 1984 and 1994 at our institutions. Favorable pathological results were defined as organ-confined disease or capsular perforation with a Gleason score of less than 7, and unfavorable pathological results were defined as capsular perforation with a Gleason score of 7 or more, seminal vesicle invasion or lymph node involvement.

Results

Overall, 18 percent of the men had PSA levels less than the standard PSA reference range (4.0 ng./ml.) compared to 22 percent when using the age-specific ranges. There were 74 more cancers detected in men younger than 60 years with the use of age-specific ranges, of which 81 percent had favorable pathological results. Among the men 60 years or older, 191 of 252 cancers (76 percent) not detected by using age-specific ranges were of favorable pathological status. Of those cancers not detected in older men with the age-specific ranges less than 3 percent were also stage T1c and 95 percent of these undetected T1c cancers were of favorable pathological status. Age-specific PSA reference ranges increased the potential for detection of prostate cancer by 18 percent in the younger men and decreased the detection by 22 percent in the older men.

Conclusions

Among these men with clinically localized prostate cancer, age-specific PSA reference ranges increased the detection of more potentially curable tumors in young men and decreased the detection of less advanced tumors in the older men compared to the standard reference range of 4.0 ng./ml. Among older men with nonpalpable (stage T1c) tumors age-specific PSA reference ranges would have detected fewer tumors. However, 95 percent of these “missed” tumors would have had favorable pathological findings.     

High Levels of Soluble p55-TNF Receptors in Seminal and Prostatic Fluids of Normal and Infertile Men

Purpose

To study the role of tumor necrosis factor (TNF) in the male reproductive system by examining the occurrence, source, and possible functional significance of soluble TNF receptors in seminal fluids of normal and infertile men.

Materials and Methods

Concentrations of soluble TNF receptors (p55-sTNF-R and p75-sTNF-R) were measured by ELISA in human sera, seminal fluids, prostatic fluid and fluid obtained from an epididymal spermatocele.

Results

The level of p55-sTNF-R in seminal fluids of normospermic men was [nearly equal] 20-fold higher than in normal serum (13.9 plus/minus 6.9 ng./ml. versus 0.7 plus/minus 0.2 ng./ml.). In contrast, p75-sTNF-R, which occurs in serum at amounts higher than p55-sTNF-R, was almost indiscernible in the seminal fluids (less than 0.18 plus/minus 0.28 ng./ml. versus 1.9 plus/minus 0.6 ng./ml. in sera). Concentrations of p55-sTNF-R in seminal fluids of oligoasthenospermic and azoospermic men were similar to those of normospermic men (15.6 plus/minus 8.5 ng./ml. and 14.9 plus/minus 6.5 ng./ml., respectively). Higher p55-sTNF-R concentrations were found in prostatic fluids and first split ejaculates (39.8 plus/minus 1.2 ng./ml. and 32 plus/minus 1.7 ng./ml., respectively), while second split ejaculates and the fluid from an epididymal spermatocele were found to contain p55-sTNF-R at lower levels (10.8 plus/minus 1 ng./ml. and 1 ng./ml., respectively).

Conclusions

These findings suggest intense local biosynthesis of p55-sTNF-R in the prostate occurring independently of spermatogenesis. Possible functional implications are: 1) shielding of spermatozoa from the inhibitory effect of TNF in the female reproductive tract; 2) a role for TNF in the normal physiology of the prostate; and 3) blocking TNF-mediated immune response in the prostate, which may have bearings on the development of prostatic hypertrophy or cancer.     

Prostate specific antigen nadir following external beam radiation therapy for clinically localized prostate Cancer: The relationship between nadir level and disease-free survival

Purpose

We determined whether the prostate specific antigen (PSA) nadir achieved following external beam radiation therapy alone predicts biochemical disease-free survival in a large cohort of men with clinically localized prostate cancer.

Materials and Methods

Between January 1986 and October 1993, 364 men with clinically localized, stages T1 to T3 adenocarcinoma of the prostate received definitive external beam radiation therapy with no prior, concomitant or adjuvant endocrine therapy. PSA was measured before treatment in 326 men (90 percent) and serial PSA was measured following treatment in all patients. All men were followed continuously for at least 24 months (median 44 months, range 24 to 90, mean 46). Biochemical failure after irradiation was defined as PSA of 1.5 ng./ml. or more and 2 consecutive serum PSA elevations.

Results

The 5-year overall biochemical disease-free survival rate for the entire group was 56 percent. PSA nadir was predictive of subsequent biochemical disease-free survival. The biochemical disease-free survival rate at 3 years was 93, 49 and 16 percent for PSA nadirs of 0 to 0.99, 1 to 1.99 and 2 or more ng./ml., respectively (p = 0.0001). In a multivariate analysis PSA nadir (0 to 0.99 versus 1.0 to 1.99 versus 2 or more ng./ml.) was an independent predictor of biochemical disease-free survival along with pretreatment PSA, central axis dose, Gleason grade and T stage.

Conclusions

PSA nadir after radiation therapy is an indicator of subsequent biochemical disease-free survival. Patients who achieve a nadir of less than 1 ng./ml. following external beam radiation therapy have a favorable biochemical disease-free survival rate, while those with a nadir of greater than 1 ng./ml. have a high subsequent failure rate. Strategies to improve results should focus on techniques to increase the likelihood of achieving a PSA nadir of less than 1 ng./ml.     

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.     

Initial Evaluation of Cyfra 21-1 Diagnostic Performances as a Urinary Marker in Bladder Transitional Cell Carcinoma

Purpose

CYFRA 21-1, an immunoradiometric assay developed for the detection of a soluble cytokeratin 19 fragment, is evaluated for its diagnostic performance in urine of patients with transitional cell carcinoma.

Materials and Methods

CYFRA 21-1 was investigated in serum and urine of 128 patients, including 48 with bladder transitional cell carcinoma (group 1), 44 with other urological pathological conditions (group 2) and 36 free of urothelial disease (group 3). Urinary cytopathology was also performed.

Results

Mean urinary CYFRA was 123.5 +/− 53, 11.9 +/− 4.8 and 2.3 +/− 0.2 ng./ml. for groups 1 to 3, respectively, and was significantly different. From the receiver operating characteristics curve, the optimal combination of 96% sensitivity and 74% specificity was determined for a threshold value of 4 ng./ml. while overall cytopathology sensitivity was 43%.

Conclusions

Urinary CYFRA 21-1 may be a useful marker for diagnosing transitional cell carcinoma.     

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.     

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.     

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.     

INCREASED URINARY HYALURONIC ACID AND INTERSTITIAL CYSTITIS

Purpose

We compared urinary levels of hyaluronic acid in patients who met the National Institute for Diabetes, and Digestive and Kidney Diseases criteria for interstitial cystitis and in age matched healthy female controls.

Materials and Methods

Urinary hyaluronic acid was measured by solid phase radiometric assay using hyaluronic acid binding protein. Hyaluronic acid and symptom scores were compared in interstitial cystitis patients who gave multiple urine samples during treatment. Since hyaluronic acid changed with treatment in some patients, 17 samples from untreated interstitial cystitis patients were selected and compared with 17 control samples.

Results

Mean plus or minus standard deviation urinary hyaluronic acid concentrations were similar in the 2 groups (interstitial cystitis group 574 ± 496, controls 512 ± 324 ng./ml., p = 0.77). When normalized to creatinine urinary hyaluronic acid was significantly higher in interstitial cystitis patients (interstitial cystitis group 674 ± 220, controls 446 ± 220 ng./mg. creatinine, p = 0.0019). Urinary creatinine concentrations did not differ significantly (interstitial cystitis group 842 ± 715, controls 1,162 ± 516 mg./l., p = 0.12).

Conclusions

Urinary hyaluronic acid was higher in interstitial cystitis patients than healthy controls. Since bladder hyaluronic acid is below the epithelium, this finding may indicate leakage across the epithelium into the urine in interstitial cystitis patients.     

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.     

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.     

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.     

Prospective Evaluation of Prostate Specific Antigen and Prostate Specific Antigen Density in the Detection of Nonpalpable and Stage T1C Carcinoma of the Prostate

Purpose

We evaluated prospectively prostate specific antigen (PSA) and prostate specific antigen density in the detection of prostate cancer in patients with normal findings on digital rectal examination with and without normal transrectal ultrasound.

Materials and Methods

Consecutive patients (184) with an elevated serum PSA and normal digital rectal examination underwent transrectal ultrasound with lesion directed and systematic biopsies (6 if prostatic volume was 50 cc or less and 12 if volume was more than 50 cc). Receiver operating characteristic curves, predictive values and likelihood ratios were calculated for PSA and PSA density.

Results

Of the 184 patients 50 (27 percent) with a normal digital rectal examination had cancer compared to 30 of 112 (27 percent) with a normal digital rectal examination and transrectal ultrasound. Median PSA or PSA density did not differ between the positive and negative biopsy groups among patients with a normal digital rectal examination (8.4 versus 7.1 and 0.22 versus 0.14 ng./ml., respectively) or a normal digital rectal examination and transrectal ultrasound (8.2 versus 7.5 and 0.21 versus 0.14 ng./ml., respectively). PSA density was superior to PSA by receiver operating characteristic analysis for cancer detection when all PSA values or those between 4 and 20 ng./ml. were considered. However, the significance was lost for a PSA of 4 to 10 ng./ml. Likelihood ratios demonstrated insignificant changes in the post-test probability if PSA density was used to determine the need for biopsy and many cancers would have been missed.

Conclusions

PSA density should not be used to determine the need for biopsy in patients with a normal digital rectal examination and/or transrectal ultrasound.     

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.     

Interferons Modify in Vitro Proliferation of Human Bladder Transitional Cell Carcinoma in the Presence of Doxorubicin and Mitomycin C

Purpose

The aim of the present study was to investigate whether interferons with their known antitumor activity modify the response of human bladder carcinoma cells to antitumor drugs.

Materials and Methods

We investigated the in vitro effect of doxorubicin, mitomycin C and the interferons alpha and gamma on cell proliferation in human bladder carcinoma cell lines as measured by 5-bromo-2'-deoxy-uridine (BrdU) incorporation.

Results

Exposure of RT 112 (but not EJ 28) cells for 2 hours to doxorubicin (500 ng./ml.) and mitomycin C (200 ng./ml.) reduced the proliferation rate to 85.9 plus/minus 3.3 percent (n = 4) and 89.3 plus/minus 4.0 percent (n = 4) of control. Treatment for 2 days with interferon alpha and gamma up to the highest concentration (200 U/ml.) showed no effect. The combination of 100 U/ml. interferon alpha and doxorubicin decreased proliferation significantly. At 50 ng./ml. the proliferation rate was decreased to 88.0 plus/minus 5.7 percent of control and at 500 ng./ml. to 67.7 plus/minus 3.1 percent. Thus interferon alpha seems to increase the sensitivity of the cells to doxorubicin. Cells treated with 20 ng./ml. mitomycin C after pretreatment with interferon alpha showed a dramatic decrease in cell proliferation (from 98.8 plus/minus 2.1 percent to 80.2 plus/minus 4.0 percent of control). This decrease was similar in the presence of 200 ng./ml. mitomycin C. Thus mitomycin C seems to render cells more sensitive to the antiproliferative action of interferon alpha. Interferon gamma had only minor effects on the response of the cells to doxorubicin or mitomycin C.

Conclusions

These studies suggest that exposure to interferon alpha increases the efficacy of anticancer drugs in vitro, probably by several mechanisms. Potential consequences of this finding for the therapeutic regime employed for treatment of bladder carcinoma are discussed.