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Background
The FDA has approved serum PSA for use as a prostate cancer screening laboratory test. Like so many serum tumor markers, it is produced by both normal and cancerous glands. In men with prostate cancer, the serum levels can be elevated with both localized and advanced or disseminated disease. PSA levels are generally proportional to the volume of the cancer. Like any laboratory test, there is a significant overlap between PSA levels found in cancer and benign prostatic hyperplasia. Thus, it is important to obtain sequential levels in low or borderline elevated values. A rise in the level as compared to an earlier measurement is an ominous sign.
The introduction of free PSA (fPSA) testing has introduced a greater level of specificity in identifying early prostate cancer. In 1998, the FDA approved fPSA testing as a diagnostic aid for men with total PSA values between 4.0-10.0 ng/mL. This has often been the diagnostic gray zone for total PSA testing and fPSA may aid in the stratification. In general, “At any percent free PSA level, one could be a lot more reassured in the man with the small prostate…if somebody has a really low percent free PSA, 10 or 12, no matter how big or how small their prostate is, then you worry. And if a patient has a really high free PSA, say 30%, no matter how big or small his prostate is, you can feel reassured.”
(William Catalona, M.D., Urologist at Barnes Hosptial, Washington University, St. Louis)But fPSA levels between 10-25% are another gray zone as the table illustrates. Additional testing on the horizon includes complexed PSA and human glandular kallikrein (hK2) to fPSA ratio.
Probability of Prostate Cancer Based Upon Test Results (Modified from Hybridech, Inc.)
Standard PSA Probability of cancer Percent free PSA Probability of cancer 0-2 ng/mL 1% 0-10% 56% 2-4 ng/mL 15% 10-15% 28% 4-10 ng/mL 25% 15-20% 20% >10 ng/mL >50% 20-25% 16% >25% 8% OUTLINE
Measurement Clinical Utility Interference Commonly Used Terms Internet Links
CLINICAL UTILITY CHARACTERIZATION
Robin T. Vollmer, MD
This article introduces the use of Bayes probability rule to calculate age and serum prostate-specific antigen (PSA)-specific positive predictive values (PPVs) for prostate cancer. The PPV is the conditional probability of having prostate cancer, given a value of PSA and a particular age group.
The formulation uses values of sensitivity obtained from previously reported studies of more than 2,700 men with prostate cancer, and it uses values of specificity obtained from previously reported studies of more than 99,000 men without prostate cancer. The formulation also introduces the use of a population-based and age-specific probability of prostate cancer, and for this it relies on the National Cancer Institute–sponsored Surveillance, Epidemiology and End Results data. The Bayes PPV suggests that in younger men, cut points defining an elevated PSA level should be raised rather than lowered.
The Bayes formulation also provides estimates of the PPV for narrow intervals of PSA, and these tabulated results may provide useful guidelines for the implications of serum PSA levels at specific age groups.
- Maximum tumor diameter is an independent predictor of prostate-specific antigen recurrence in prostate cancer.
Eichelberger LE, Koch MO, Eble JN, Ulbright TM, Juliar BE, Cheng L.
1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Mod Pathol. 2005 Jul;18(7):886-90. Abstract quote
Maximum tumor diameter has been shown to correlate with multiple predictors of clinical outcome in prostate cancer. In the current study, we prospectively analyze whether maximum tumor diameter is a significant predictor of prostate-specific antigen (PSA) recurrence.
The study population consisted of 364 patients who underwent radical prostatectomy for prostate cancer. Prostatectomy specimens were evaluated by whole-mount processing of the entire prostate. Maximum tumor diameter was measured from the whole-mount sections of the prostate. Spearman's coefficient of rank correlation was used to correlate tumor diameter with continuous variables. T-tests or analysis of variance (ANOVA) tests were performed to determine if tumor diameter was significantly associated with other clinical and pathologic variables.
The effect of clinical and pathologic variables on time to recurrence was analyzed using Cox regression. The mean tumor diameter for all patients was 1.73 cm (range, 0.02-4.40 cm). Maximum tumor diameter was associated with preoperative PSA (r=0.22, P<0.0001), prostate weight (r=-0.12, P=0.028), tumor volume (r=0.87, P<0.0001), Gleason score (r=0.29, P<0.0001), and pathologic stage (P<0.0001). Cox multiple regression was performed to test the prognostic value of maximum tumor diameter adjusting for pathologic stage, Gleason score, and surgical margin status.
Increased maximum tumor diameter was associated with shorter time to PSA recurrence (hazard ratio=1.70, 95% confidence interval 1.13-2.56, P=0.01), controlling for risk factors, Gleason score, and surgical margin status.
We conclude that maximum tumor diameter is a significant predictor of biochemical recurrence in patients with prostate cancer.
- Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower.
Thompson IM, Ankerst DP, Chi C, Lucia MS, Goodman PJ, Crowley JJ, Parnes HL, Coltman CA Jr.
Department of Urology, University of Texas Health Science Center at San Antonio, TX 78229, USA.
JAMA. 2005 Jul 6;294(1):66-70. Abstract quote
CONTEXT: Three fourths of US men older than 50 years have been screened with prostate-specific antigen (PSA) for prostate cancer.
OBJECTIVE: To estimate the receiver operating characteristic (ROC) curve for PSA.
DESIGN, SETTING, AND PARTICIPANTS: Calculation of PSA ROC curves in the placebo group of the Prostate Cancer Prevention Trial, a randomized, prospective study conducted from 1993 to 2003 at 221 US centers. Participants were 18 882 healthy men aged 55 years or older without prostate cancer and with PSA levels less than or equal to 3.0 ng/mL and normal digital rectal examination results, followed up for 7 years with annual PSA measurement and digital rectal examination. If PSA level exceeded 4.0 ng/mL or rectal examination result was abnormal, a prostate biopsy was recommended. After 7 years of study participation, an end-of-study prostate biopsy was recommended in all cancer-free men.
MAIN OUTCOME MEASURES: Operating characteristics of PSA for prostate cancer detection, including sensitivity, specificity, and ROC curve.
RESULTS: Of 8575 men in the placebo group with at least 1 PSA measurement and digital rectal examination in the same year, 5587 (65.2%) had had at least 1 biopsy; of these, 1225 (21.9%) were diagnosed with prostate cancer. Of 1213 cancers with Gleason grade recorded, 250 (20.6%) were Gleason grade 7 or greater and 57 (4.7%) were Gleason grade 8 or greater. The areas under the ROC curve (AUC) for PSA to discriminate any prostate cancer vs no cancer, Gleason grade 7 or greater cancer vs no or lower-grade cancer, and Gleason grade 8 or greater cancer vs no or lower-grade cancer were 0.678 (95% confidence interval [CI], 0.666-0.689), 0.782 (95% CI, 0.748-0.816), and 0.827 (95% CI, 0.761-0.893), respectively (all P values <.001 for AUC vs 50%). For detecting any prostate cancer, PSA cutoff values of 1.1, 2.1, 3.1, and 4.1 ng/mL yielded sensitivities of 83.4%, 52.6%, 32.2%, and 20.5%, and specificities of 38.9%, 72.5%, 86.7%, and 93.8%, respectively. Age-stratified analyses showed slightly better performance of PSA in men younger than 70 years vs those 70 years or older with AUC values of 0.699 (SD, 0.013) vs 0.663 (SD, 0.013) (P = .03).
CONCLUSION: There is no cutpoint of PSA with simultaneous high sensitivity and high specificity for monitoring healthy men for prostate cancer, but rather a continuum of prostate cancer risk at all values of PSA.
Robin T. Vollmer, MD
Many aspects of prostate cancer differ between black men and white men, including incidence, stage, grade, sensitivities and specificities of serum prostate-specific antigen (PSA) levels, and survival. In general, the level of serum PSA reflects the mass of the prostate and the amount of tumor present, but the question to consider is whether this relationship is the same for blacks as for whites. If it is the same, then the ways we use serum PSA to screen, stage, and follow up white men with cancer should work equally for black men. If it is not, then we need alternative strategies for using serum PSA levels in blacks.
I used regression analysis to study how the serum PSA level depends on prostate mass and the amount of tumor in 194 American veterans, including 87 black men.
I found that black men produced higher levels of serum PSA for any given amount of tumor compared with whites, and I demonstrated that this difference can significantly affect the assessment of risk for outcomes in blacks.
Serum percent-free PSA does not predict extraprostatic spread of prostate cancer.
Henricks WH, England BG, Giacherio DA, Oesterling JE, Wojno KJ.
Department of Pathology, The University of Michigan Medical Center, Ann Arbor 48109-0054, USA.
Am J Clin Pathol 1998 May;109(5):533-9 Abstract quote Percent-free prostate-specific antigen (proportion of free prostate-specific antigen [PSA] to total PSA) has been shown recently in studies on frozen serum samples to be more useful than total PSA alone in distinguishing prostate cancer from benign conditions of the prostate gland.
The primary purpose of our study was to determine whether percent-free PSA could predict extraprostatic spread of prostate cancer. We also sought to evaluate the freeze-thaw stability of free PSA. Percent-free PSA values in fresh serum samples were compared with those in aliquots subjected to one to five freeze-thaw cycles. Percent-free PSA values in frozen serum samples from 130 men undergoing radical prostatectomy for clinically localized prostate cancer were compared across pathologic stages. Free PSA levels remained stable for up to five freeze-thaws. Great overlap was found in percent-free PSA values for men with organ-confined disease and those with extraprostatic spread.
These results indicate that multiple freeze-thaw cycles do not significantly affect free PSA levels and percent-free PSA is not useful in identifying ideal candidates for radical prostatectomy.
Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial.
Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A, Richie JP, deKernion JB, Walsh PC, Scardino PT, Lange PH, Subong EN, Parson RE, Gasior GH, Loveland KG, Southwick PC.
Division of Urologic Surgery, Washington University School of Medicine, St Louis, MO 63110, USA.
JAMA 1998 May 20;279(19):1542-7 Abstract quote
CONTEXT: The percentage of free prostate-specific antigen (PSA) in serum has been shown to enhance the specificity of PSA testing for prostate cancer detection, but earlier studies provided only preliminary cutoffs for clinical use.
OBJECTIVE: To develop risk assessment guidelines and a cutoff value for defining abnormal percentage of free PSA in a population of men to whom the test would be applied.
DESIGN: Prospective blinded study using the Tandem PSA and free PSA assays (Hybritech Inc, San Diego, Calif).
SETTING: Seven nationwide university medical centers.
PARTICIPANTS: A total of 773 men (379 with prostate cancer, 394 with benign prostatic disease) 50 to 75 years of age with a palpably benign prostate gland, PSA level of 4.0 to 10.0 ng/mL, and histologically confirmed diagnosis.
MAIN OUTCOME MEASURES: A percentage of free PSA cutoff that maintained 95% sensitivity for prostate cancer detection, and probability of cancer for individual patients.
RESULTS: The percentage of free PSA may be used in 2 ways: as a single cut-off (ie, perform a biopsy for all patients at or below a cutoff of 25% free PSA) or as an individual patient risk assessment (ie, base biopsy decisions on each patient's risk of cancer). The 25% free PSA cutoff detected 95% of cancers while avoiding 20% of unnecessary biopsies. The cancers associated with greater than 25% free PSA were more prevalent in older patients, and generally were less threatening in terms of tumor grade and volume. For individual patients, a lower percentage of free PSA was associated with a higher risk of cancer (range, 8%-56%). In the multivariate model used, the percentage of free PSA was an independent predictor of prostate cancer (odds ratio [OR], 3.2; 95% confidence interval [CI], 2.5-4.1; P < .001) and contributed significantly more than age (OR, 1.2; 95% CI, 0.92-1.55) or total PSA level (OR, 1.0; 95% CI, 0.92-1.11) in this cohort of subjects with total PSA values between 4.0 and 10.0 ng/mL.
CONCLUSIONS: Use of the percentage of free PSA can reduce unnecessary biopsies in patients undergoing evaluation for prostate cancer, with a minimal loss in sensitivity in detecting cancer. A cutoff of 25% or less free PSA is recommended for patients with PSA values between 4.0 and 10.0 ng/mL and a palpably benign gland, regardless of patient age or prostate size. To our knowledge, this study is the largest series to date evaluating the percentage of free PSA in a population representative of patients in whom the test would be used in clinical practice.
Prediction of post-radical prostatectomy pathological outcome for stage T1c prostate cancer with percent free prostate specific antigen: a prospective multicenter clinical trial.
Southwick PC, Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A, Richie JP, Walsh PC, Scardino PT, Lange PH, Gasior GH, Parson RE, Loveland KG.
Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
J Urol 1999 Oct;162(4):1346-51 Abstract quote
PURPOSE: Prostate specific antigen (PSA) exists in bound (complexed) and unbound (free) forms in serum. The percentage of free PSA enhances the specificity of PSA testing for prostate cancer detection. We evaluated the use of percent free PSA preoperatively to predict pathological stage.
MATERIALS AND METHODS: A total of 379 men with prostate cancer and 394 with benign prostatic disease 50 to 75 years old were enrolled in this prospective study at 7 medical centers. All subjects had a palpably benign prostate gland, serum PSA 4.0 to 10.0 ng./ml. and a histologically confirmed diagnosis. The Hybritech Tandem PSA and free PSA assays were used. Of the 379 cancer patients 268 (71%) underwent radical prostatectomy.
RESULTS: Higher percent free PSA levels were associated with more favorable histopathological findings in prostatectomy specimens. A value of 15% free PSA provided the greatest discrimination in predicting favorable pathological outcome. Organ confined cancer, Gleason sum less than 7 and small tumors (10% or less involvement of the prostate) were noted in 75% of patients with greater than 15% and only 34% with 15% or less free PSA (p<0.001). Multivariate logistic regression analysis revealed percent free PSA to be the strongest predictor of postoperative pathological outcome (odds ratio 2.25), followed by biopsy Gleason sum (2.06) and patient age (1.35). Total PSA was not predictive in this cohort but has been shown in prior studies to be predictive of outcome when a broader range of PSA values is evaluated.
CONCLUSIONS: Percent free PSA may be used for risk assessment of the presence (diagnosis) and stage of prostate cancer in men with PSA between 4 and 10 ng./ml. Percent free PSA may be combined with PSA, digital rectal examination and biopsy findings to help predict postoperative pathological stage and grade, and may assist the patient and physician in making more informed treatment decisions.
Comparison of percent free PSA, PSA density, and age-specific PSA cutoffs for prostate cancer detection and staging.
Catalona WJ, Southwick PC, Slawin KM, Partin AW, Brawer MK, Flanigan RC, Patel A, Richie JP, Walsh PC, Scardino PT, Lange PH, Gasior GH, Loveland KG, Bray KR.
Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Urology 2000 Aug 1;56(2):255-60 Abstract quote
OBJECTIVES: Various methods have been proposed to increase the specificity of prostate-specific antigen (PSA), including age-specific PSA reference ranges, PSA density (PSAD), and percent free PSA (%fPSA). In this multicenter study, we compared these methods for their utility in cancer detection and their ability to predict pathologic stage after radical prostatectomy in patients with clinically localized, Stage T1c cancer.
METHODS: Seven hundred seventy-three men (379 with prostate cancer, 394 with benign prostatic disease), 50 to 75 years old, from seven medical centers were enrolled in this prospective blinded study. All subjects had a palpably benign prostate, PSA 4.0 to 10.0 ng/mL, and a histologically confirmed diagnosis. Hybritech's Tandem PSA and free PSA assays were used.
RESULTS: %fPSA and age-specific PSA cutoffs enhanced PSA specificity for cancer detection, but %fPSA maintained significantly higher sensitivities. Age-specific PSA cutoffs missed 20% to 60% of cancers in men older than 60 years of age. %fPSA and PSAD performed equally well for detection (95% sensitivity) if cutoffs of 25% fPSA or 0.078 PSAD were used. The commonly used PSAD cutoff of 0.15 detected only 59% of cancers. %fPSA and PSAD also produced similar results for prediction of the post-radical prostatectomy pathologic stage. Patients with cancer with higher %fPSA values (greater than 15%) or lower PSAD values (0.15 or less) tended to have less aggressive disease.
CONCLUSIONS: The results of this study demonstrated that cancer detection (sensitivity) is significantly higher with %fPSA than with age-specific PSA reference ranges. %fPSA and PSAD provide comparable results, suggesting that %fPSA may be used in place of PSAD for biopsy decisions and in algorithms for prediction of less aggressive tumors since the determination of %fPSA does not require ultrasound.
Percentage of free PSA in black versus white men for detection and staging of prostate cancer: a prospective multicenter clinical trial.
Catalona WJ, Partin AW, Slawin KM, Naughton CK, Brawer MK, Flanigan RC, Richie JP, Patel A, Walsh PC, Scardino PT, Lange PH, deKernion JB, Southwick PC, Loveland KG, Parson RE, Gasior GH.
Division of Urologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Urology 2000 Mar;55(3):372-6 Abstract quote
OBJECTIVES: In predominately white populations, measurement of the percentage of free prostate-specific antigen (%fPSA) has been shown to enhance the specificity of total PSA testing for prostate cancer while maintaining high sensitivity and to aid in prostate cancer staging. This study evaluated whether the %fPSA cutoff that maintained a 95% sensitivity in a white population yielded the same sensitivity and specificity in a black population and whether %fPSA was useful in predicting postoperative pathologic features in blacks.
METHODS: We evaluated 647 white and 79 black men, prospectively enrolled at prostate cancer screening and surgical referral centers. Subjects were 50 to 75 years old with digital rectal examination findings that were not suspicious for prostate cancer and total PSA values between 4.0 and 10.0 ng/mL. All had undergone needle biopsy of the prostate. Hybritech's Tandem total and free PSA assays were used.
RESULTS: Ninety-five percent sensitivity was attained with a %fPSA cutoff of 25% in both races. Use of this cutoff could have avoided unnecessary biopsies in 20% of white and 17% of black subjects (P = 0.69). In receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) for %fPSA was significantly higher than for total PSA in both blacks (0.76 versus 0.56, P <0.01) and whites (0.70 versus 0.54, P <0.001). In both races, higher %fPSA values indicated a lower risk of cancer and also predicted favorable pathologic features in radical prostatectomy specimens.
CONCLUSIONS: A 25% fPSA cutoff detected 95% of cancers and reduced unnecessary biopsies in both races. Higher %fPSA values were associated with favorable postoperative histopathologic findings in both races.
Probability of prostate cancer detection based on results of a multicenter study using the AxSYM free PSA and total PSA assays.
Vessella RL, Lange PH, Partin AW, Chan DW, Sokoll LJ, Sasse EA, Crawford ED.
University of Washington Medical School, Seattle, Washington 98195, USA.
Urology 2000 Jun;55(6):909-14 Abstract quote
OBJECTIVES: The determination of the percentage of free prostate-specific antigen (%fPSA) enhances the specificity of prostate cancer (CaP) detection. This study was undertaken to assess the performance of %fPSA in differentiating benign prostate disease from CaP and to determine the CaP probability estimates using the AxSYM Free PSA and AxSYM Total PSA assays.
METHODS: In this prospective study, 297 men, 50 years old or older, with a total PSA level between 4 and 10 ng/mL and a nonsuspicious digital rectal examination were enrolled at 10 clinical sites. All subjects underwent at least sextant prostate biopsies to establish the diagnosis. fPSA and total PSA (tPSA) levels were determined using the AxSYM Free PSA and AxSYM Total PSA assays. Percent fPSA values were compared with tPSA values to determine the appropriate cutoffs for prostate biopsy and to calculate the CaP probability estimates.
RESULTS: The strongest predictor of CaP in a logistic regression model was %fPSA (odds ratio 2.29), which contributed significantly more than age or tPSA to the predictive model. In this study population, a %fPSA cutoff of 26.4% would have detected 96% of subjects with CaP (sensitivity) and would have eliminated 27.4% of unnecessary biopsies (specificity). CaP probability estimates ranged from 9% to 69% and increased as the %fPSA value decreased. Men with a %fPSA level of 10% or lower had a 69% probability of CaP, and men with a %fPSA level of greater than 26% had a 9% probability of CaP.
CONCLUSIONS: Percent fPSA values can help differentiate CaP from benign prostate disease and reduce unnecessary biopsies in 27% of men 50 years old or older whose digital rectal examination was normal and whose tPSA level was between 4 and 10 ng/mL. A %fPSA result can assist the physician and patient in determining the probability of CaP and assessing the need for prostate biopsy.
Ratio of free or complexed prostate-specific antigen (PSA) to total PSA: which ratio improves differentiation between benign prostatic hyperplasia and prostate cancer?
Jung K, Elgeti U, Lein M, Brux B, Sinha P, Rudolph B, Hauptmann S, Schnorr D, Loening SA.
Department of Urology, University Hospital Charite, Humboldt University, Schumannstrasse 20/21, D-10098 Berlin, Germany.
Clin Chem 2000 Jan;46(1):55-62 Abstract quote
BACKGROUND: The aim of this study was to compare the diagnostic utility of a new assay that measures all forms of prostate-specific antigen complexed (cPSA) to serum proteins except alpha(2)-macroglobulin with the assay of free PSA (fPSA) and the corresponding ratios to total PSA (tPSA) to improve the differentiation between benign prostatic hyperplasia (BPH) and prostate cancer (PCa).
METHODS: Serum samples were collected from 91 men without prostate disease and with normal digital rectal examination (controls), 144 untreated patients with PCa, and 89 patients with BPH. tPSA and cPSA were measured using the Bayer Immuno 1 system; fPSA and the additional tPSA were measured with the Roche Elecsys system.
RESULTS: The median cPSA/tPSA, fPSA/tPSA, and fPSA/cPSA ratios were significantly different between patients with BPH and PCa (78.7% vs 90.7%, 25.5% vs 12.1%, and 36.8% vs 14.3%, respectively; P <0.001). No correlations of cPSA and its ratios to tumor stage and grade were found. ROC analysis showed that cPSA was not different from tPSA (areas under the curve, 0.632 vs 0.568), whereas the cPSA/tPSA ratio was similar to the fPSA/tPSA ratio in increasing discrimination between BPH and PCa patients with tPSA concentrations in the tPSA gray zone between 2 and 10 &mgr;g/L (areas under the curve, 0.851 vs 0.838).
CONCLUSIONS: Compared with tPSA, the fPSA/tPSA and cPSA/tPSA ratios both improve the differentiation between BPH and PCa comparably and are similarly effective in reducing the rate of unnecessary biopsies, whereas cPSA alone does not have any effect.
Total PSA, free PSA/total PSA ratio, and molecular PSA detection in prostate cancer: which is clinically effective and when?
Basso D, Fogar P, Piva MG, Navaglia F, Mazza S, Prayer-Galetti T, Castellucci E, Pagano F, Plebani M.
Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy.
Urology 2000 May;55(5):710-5 Abstract quote
OBJECTIVES: To ascertain when the serum determination of the free prostate-specific antigen (PSA)/total PSA (fPSA/tPSA) ratio is clinically useful, and whether the identification of PSA or prostate-specific membrane antigen (PSM) mRNA in circulating cells has diagnostic advantages over the determination of their protein product.
METHODS: fPSA, tPSA, and the fPSA/tPSA ratio were determined in the sera of 50 men with benign nonprostatic urologic diseases (EPD), 112 patients with prostate cancer (PCa), and 218 with benign prostatic hyperplasia (BPH). mRNA was extracted from the circulating mononuclear cells of 13 EPD samples, 25 PCa samples, and 38 BPH samples. PSA and PSM mRNA signals were identified in these samples by means of reverse transcriptase-polymerase chain reaction.
RESULTS: Overall, at a fixed specificity of 95%, the sensitivity of tPSA was 19% and that of the fPSA/tPSA ratio was 40% in distinguishing PCa from BPH. The fPSA/tPSA ratio allowed the discrimination of PCa from BPH with satisfactory sensitivity and specificity when considering patients less than 60 years of age (100% and 95%, respectively). PSA and PSM mRNA were positive in 1 and 7 of 13 EPD samples, 6 and 13 of 25 PCa samples, and 6 and 17 of 38 BPH samples. The Gleason score did not correlate with tPSA, the fPSA/tPSA ratio, PSA mRNA, or PSM mRNA.
CONCLUSIONS: The serum determination of the fPSA/tPSA ratio is an excellent index of PCa for subjects younger than 60 years of age; the clinical utility of PSA mRNA identification in circulating cells needs to be validated by large follow-up studies, and the analysis of PSM mRNA seems to be of no clinical interest.
Ratio of free-to-total prostate specific antigen correlates with tumor volume in patients with increased prostate specific antigen.Grossklaus DJ, Shappell SB, Gautam S, Smith JA Jr, Cookson MS.
Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
J Urol 2001 Feb;165(2):455-8 Related Articles, Books, LinkOut
Ratio of free-to-total prostate specific antigen correlates with tumor volume in patients with increased prostate specific antigen.Grossklaus DJ, Shappell SB, Gautam S, Smith JA Jr, Cookson MS.
Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
PURPOSE: We evaluated the relationship between the ratio of free-to-total prostate specific antigen (PSA) and prostate pathology, including grade, stage and tumor volume, among patients with prostate cancer who underwent radical prostatectomy. MATERIALS AND METHODS: We prospectively analyzed 54 consecutive patients with prostate cancer who underwent radical prostatectomy and in whom frozen serum was available for assessment of free-to-total PSA ratio. Pathological review was done with whole mount sections, and total tumor volume was determined by planimetry. Comparison between free-to-total PSA ratio and pathological parameters was performed using the Pearson correlation coefficient. RESULTS: Among the 54 patients mean total and free-to-total PSA ratio were 5.81 and 14.2 ng./ml., respectively, and free-to-total PSA ratio directly correlated with prostate volume (p = 0.037), and inversely correlated with Gleason score (p = 0.012) and extracapsular disease (p = 0.0074). Furthermore, there was a significant relationship between free-to-total PSA ratio and pathological stage pT2a/b in 39 cases versus pT3a/b in 15 (p = 0.005). Overall, there was no correlation between free-to-total PSA ratio and tumor volume. However, among 37 patients with an increased PSA, defined as greater than 4.0 ng./ml., a significant inverse relationship between free-to-total PSA ratio and tumor volume was identified (p = 0.01). Among this subset there was only a weak correlation with prostate volume (p = 0.049).
CONCLUSIONS: Our findings suggest that free-to-total PSA ratio may be predictive of tumor biology among those patients with a total PSA of greater than 4 ng./ml. as evidenced by good correlation with tumor grade and volume. This finding appears to be independent of prostate volume. These preliminary results suggest the need for additional studies among patients with an increased PSA designed to evaluate the potential role of free-to-total PSA ratio in combination with traditional clinical variables in the prediction of prostate cancer pathology.
Contemporary use of complexed PSA and calculated percent free PSA for early detection of prostate cancer: impact of changing disease demographics.
Miller MC, O'Dowd GJ, Partin AW, Veltri RW.
UroCor, Inc., Oklahoma City, Oklahoma, USA
Urology 2001 Jun;57(6):1105-1111 Abstract quote
Objectives. To assess the diagnostic performance of complexed prostate-specific antigen (cPSA), total PSA (tPSA), and calculated free/total PSA (f/t PSA) ratios in the differentiation of benign disease from prostate cancer (CaP) using a contemporary patient cohort.
Methods. The cPSA, tPSA, and calculated fPSA values were determined using the Bayer Immuno-1 system. To validate our calculated f/t PSA ratio, we also retrospectively measured fPSA using the Abbott AxSYM immunoassay system in archival pretreatment sera obtained between 1990 and 1997 from 362 men with clinically and biopsy-confirmed benign prostatic hyperplasia (n = 179) or CaP (n = 183). The diagnostic utility of tPSA, cPSA, and the calculated f/t PSA ratio was assessed using a contemporary test population consisting of sera prospectively collected between June 1999 and June 2000 from 3006 men who had recently undergone a systematic biopsy by urologists in clinical practices throughout the United States. This contemporary patient sample had biopsy diagnoses of either no evidence of malignancy (n = 1857) or CaP (n = 1149). All serum samples had tPSA values between 2.0 and 20.0 ng/mL.
Results. The measured versus calculated f/t PSA ratios had a Pearson's correlation coefficient of 0.9130 in the retrospectively studied population of 362 men. The areas under the receiver operating characteristic curves (ROC-AUCs) for the measured and calculated f/t PSA ratios were indistinguishable (69.6% versus 69.2%, respectively). In the contemporary population (n = 3006), the ROC-AUC for tPSA, cPSA, and the calculated f/t PSA ratio was 52.2%, 53.9%, and 58.4%, respectively. We also compared the diagnostic performance using published cutoffs for tPSA (greater than 4.0 ng/mL), cPSA (greater than 3.8 ng/mL), and the f/t PSA ratio (greater than 15% and greater than 25%) in tPSA reflex ranges of 2 to 20 ng/mL and 2 to 10 ng/mL. We found that both cPSA and the f/t PSA ratio (greater than 25% cutoff) outperformed tPSA and yielded similar results in terms of biopsies spared and cancers missed.
Conclusions. The calculated f/t PSA ratio and cPSA perform equally well in terms of the improvement of specificity in the discrimination of benign disease and CaP. The f/t PSA ratio and cPSA provide clinical benefits over the use of tPSA alone, such as an increased sparing of unnecessary biopsies performed with a manageable degree of risk of delayed cancer detection.
Impact of preoperative serum PSA level from 0 to 10 ng/ml on pathological findings and disease-free survival after radical prostatectomy.
Shekarriz B, Upadhyay J, Bianco FJ Jr, Tefilli MV, Tiguert R, Gheiler EL, Grignon DJ, Pontes JE, Wood DP Jr.
Department of Urology, Wayne State University and School of Medicine, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA.
Prostate 2001 Aug 1;48(3):136-43 Abstract quote
BACKGROUND: To determine the impact of various preoperative serum prostate specific antigen (PSA) levels in the range from 0.1 to 10 ng/ml on pathological stage and disease-free survival after radical prostatectomy.
METHODS: We selected a cohort of 585 patients who underwent radical prostatectomy between 1991-1996 for clinically localized prostate cancer and presented with preoperative serum PSA levels from 0.1 to 10 ng/ml.
RESULTS: Pathological organ-confined disease was present in 57.6% of patients. The rate of organ-confined disease decreased from an average of 85% for patients with a PSA value < 2 ng/ml, to 46.8% for patients with a PSA value > 7 ng/ml. We found statistically significant correlations between preoperative serum PSA level and overall pathological stage (P = 0.001), pathologically organ-confined disease (P = 0.001), margin positive rates (P = 0.001), extra prostatic extension (P = 0.001), and seminal vesicle invasion (P = 0.001). The overall disease-free survival rate was 87%, with a median follow up of 42.4 months. Disease free survival was significantly better for patients with PSA up to 4 ng/ml (P = 0.005).
CONCLUSIONS: Our data suggests that PSA detection programs should strive to detect prostate cancer in men before the PSA level rises above 7 ng/ml. In addition, since patients with a PSA level < 4 ng/ml had better disease-free survival rates than those with a PSA level between 4.1-10 ng/ml, eliminating an arbitrary cutoff of 4 ng/ml, may lead to improved disease-free survival.
A prospective study to evaluate the role of complexed prostate specific antigen and free/total prostate specific antigen ratio for the diagnosis of prostate cancer.
Mitchell ID, Croal BL, Dickie A, Cohen NP, Ross I.
Department of Urology, Grampian University Hospitals Trust and Health Services Research Unit, University of Aberdeen, Aberdeen, United Kingdom.
J Urol 2001 May;165(5):1549-53 Abstract quote
PURPOSE: Patients are increasingly undergoing prostatic biopsy to identify localized prostate cancer. The decision to perform a biopsy is often made on the basis of total prostate specific antigen (PSA). However, this value lacks adequate specificity for this task. We evaluate the role that a number of these tests, including the Bayer complexed PSA (Bayer Diagnostics, Tarrytown, New York) and free/total PSA ratio, may have in our clinical practice.
MATERIALS AND METHODS: A total of 160 consecutive patients attending a prostate assessment clinic were enrolled during an 18-month period in our study. All patients had a previously recorded total PSA (range 2.6 to 20.0 ng./ml.). Before transrectal ultrasound biopsy of the prostate gland, a blood sample was taken with patient consent. The findings on ultrasound were then recorded, including prostate volume. Serum samples were immediately sent for subsequent storage and analysis.
RESULTS: Of the patients enrolled 109 had benign histology while 51 had prostatic carcinoma. The 2 patient groups were well matched for age. In our series patients with prostate cancer had significantly smaller prostates and higher mean total PSA. At a high sensitivity, such as 95%, it appeared that Bayer complexed PSA performed better than the other tests and ratios, with an estimated specificity of 24.8% compared with 17.4% for Bayer total PSA and 15.6% for Abbott free/total PSA (Abbott Laboratories, Abbott Park, Illinois). Receiver operator characteristics curves were drawn, and when the areas under them were calculated, we demonstrated that the area under the curve for Bayer complexed PSA (0.706) was between the values for total PSA (0.671) and free/total PSA ratio (0.731). However, the only statistically significant improvement in performance was in Bayer complexed PSA over the total PSA assays.
CONCLUSIONS: Our study revealed that the overall diagnostic performance of Bayer complexed PSA appears to be better than the other PSA tests and ratios studied. The use of Bayer complexed PSA may lead to a reduction in the number of men undergoing unnecessary prostatic biopsy.
Predictive value of total and percent free prostate specific antigen in high grade prostatic intraepithelial neoplasia lesions: results of the Tyrol Prostate Specific Antigen Screening Project.
Horninger W, Volgger H, Rogatsch H, Strohmeyer D, Steiner H, Hobisch A, Klocker H, Bartsch G.
Department of Urology, University of Innsbruck, Innsbruck, Austria.
J Urol 2001 Apr;165(4):1143-5 Abstract quote
PURPOSE: We evaluate the predictive values of total and percent free prostate specific antigen (PSA) in regard to high grade intraepithelial lesions in volunteers who participated in the Tyrol PSA Screening Project.
MATERIALS AND METHODS: Between June 1995 and December 1998, 1,474 patients undergoing transrectal biopsy of the prostate were evaluated. The primary detection rates of prostate cancer and high grade intraepithelial lesions were evaluated. In addition, the rate of prostate cancer detected on biopsy in patients diagnosed with high grade prostatic intraepithelial neoplasia on the previous biopsy was assessed. Mean total PSA values and mean percent free PSA levels were determined for each study group and compared using the Mann-Whitney U test.
RESULTS: A total of 1,077 (73.1%) volunteers had benign prostatic hyperplasia or prostatitis, and 327 (22.2%) had prostate cancer. The primary detection rate for high grade intraepithelial lesions was 4.7% (70 patients) and on repeat biopsy was 38.6% (27). Mean total PSA for the benign prostatic hyperplasia, prostate cancer, high grade and intraepithelial cancer groups were 6.0, 8.7, 5.9 and 5.2 ng./ml., respectively. Mean percent free PSA values for the various groups were 21.9, 12.1, 15.0 and 12.0, respectively. In regard to total PSA there was a statistically significant difference between the prostate cancer and high grade prostatic intraepithelial neoplasia groups (p = 0.016), as well as the prostate cancer and intraepithelial cancer groups (p = 0.028). However, the high grade and intraepithelial cancer groups did not differ significantly. In regard to percent free PSA there were statistically significant differences between the prostate cancer and high grade prostatic intraepithelial neoplasia groups (p = 0.0001), and the high grade and intraepithelial cancer groups (p = 0.013).
CONCLUSIONS: In regard to percent free PSA our data indicate a significant difference between high grade intraepithelial lesion and intraepithelial cancer. Due to a substantial overlap in percent free prostate specific antigen between the 2 groups, a clinically useful cutoff point could not be established. Therefore, we recommend repeat biopsy in all patients with high grade intraepithelial lesions regardless of the percent free PSA.
Tumor volume in prostate cancer and serum prostate-specific antigen. Analysis from a kinetic viewpoint.Vollmer RT, Humphrey PA.
Veterans Affairs Medical Center, Department of Pathology, Duke University Medical Center, Durham, NC, USA.
Am J Clin Pathol 2003 Jan;119(1):80-9 Abstract quote Many have observed poor correlations between serum prostate-specific antigen (PSA) and tumor volume, and this noise undoubtedly reduces the diagnostic specificity of PSA. To explore this phenomenon, we addressed the problem from a theoretical viewpoint. Specifically, we used a compartmental model and first-order kinetics to develop the mathematics necessary to relate serum PSA to tumor volume.
We found that the resulting model fit well the observed kinetic data of PSA measured after biopsy or prostatectomy. The model also predicted a linear relationship between PSA and the sum of volumes of benign and malignant tissues, but the coefficients for this linear equation are more complex than previously thought. They reflect not only how much PSA may be present in each tissue but also 3 rate parameters and the volume of serum. Much of the noise in the linkage between PSA and tumor volume is due to individual patient differences in the 3 rate parameters and in serum volume.
Our model predicts that without ways to directly measure the several involved rate parameters, we will not be able to accurately predict tumor volume from PSA. Nevertheless, surrogates for the missing parameters may exist and could lead to statistical models that could improve the prediction of tumor volume.
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Free PSA-PSA is present in the serum as both bound to proteins and unbound, or free. It is the free component which appears to be more sensitive and specific for PSA testing for cancer. In general, high levels of free PSA are associated with benign prostatic hyperplasia and low levels are associated with prostate cancer. Note that this is the opposite to expected results with measurement of total PSA.
LHRH agonists-This is a class of prostate cancer drugs which manipulates the body's production of androgens (testosterone), by decreasing it. Prostate cancer, like breast cancer, is hormonally sensitive, that is, it depends upon androgen hormones for growth. By decreasing production, the growth of the prostate cancer is appreciably slowed.
PAP-Stands for prostate acid phosphatase. Before PSA, this serum test was used as a surrogate marker for prostate cancer. It is less specific and sensitive for the detection of prostate cancer and has largely been supplanted by serum PSA measurements.
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