Purpose

Prostate specific antigen (PSA) velocity has been proposed as a marker to aid detection of prostate cancer. We sought to determine whether PSA velocity could predict the results of repeat biopsy in men with persistently elevated PSA after initial negative biopsy.

Materials and Methods

We identified 1,837 men who participated in the Göteborg or Rotterdam section of the European Randomized Screening study of Prostate Cancer (ERSPC), and who had one or more subsequent prostate biopsies after an initial negative finding. We evaluated whether PSA velocity improved predictive accuracy beyond that of PSA alone.

Results

There were a total of 2579 repeat biopsies, of which 363 (14%) were positive for prostate cancer, and 44 (1.7%) were high grade (Gleason score ≥7). Although PSA velocity was statistically associated with cancer risk (p<0.001), it had very low predictive accuracy (area-under-the-curve [AUC] of 0.55). There was some evidence that PSA velocity improved AUC compared to PSA for high grade cancer. However, the small increase in risk associated with high PSA velocity – from 1.7 % to 2.8% as velocity increased from 0 to 1 ng / ml / year - is of questionable clinical relevance.

Conclusions

Men with a prior negative biopsy have a lower risk for prostate cancer at subsequent biopsies, with high grade disease particularly rare. We found little evidence to support the use of PSA velocity to aid decisions about repeat biopsy for prostate cancer.

Objectives

To compare the predictive performance and potential clinical usefulness of risk calculators of the European Randomized Study of Screening for Prostate Cancer (ERSPC RC) with and without information on prostate volume.

Methods

We studied 6 cohorts (5 European and 1 US) with a total of 15,300 men, all biopsied and with pre-biopsy TRUS measurements of prostate volume. Volume was categorized into 3 categories (25, 40, and 60 cc), to reflect use of digital rectal examination (DRE) for volume assessment. Risks of prostate cancer were calculated according to a ERSPC DRE-based RC (including PSA, DRE, prior biopsy, and prostate volume) and a PSA + DRE model (including PSA, DRE, and prior biopsy). Missing data on prostate volume were completed by single imputation. Risk predictions were evaluated with respect to calibration (graphically), discrimination (AUC curve), and clinical usefulness (net benefit, graphically assessed in decision curves).

Results

The AUCs of the ERSPC DRE-based RC ranged from 0.61 to 0.77 and were substantially larger than the AUCs of a model based on only PSA + DRE (ranging from 0.56 to 0.72) in each of the 6 cohorts. The ERSPC DRE-based RC provided net benefit over performing a prostate biopsy on the basis of PSA and DRE outcome in five of the six cohorts.

Conclusions

Identifying men at increased risk for having a biopsy detectable prostate cancer should consider multiple factors, including an estimate of prostate volume.

PURPOSE

The relationship between prostate specific antigen (PSA) level and prostate cancer risk remains subject to fundamental disagreements. We hypothesize that the risk of prostate cancer on biopsy for a given PSA level is affected by identifiable characteristics of the cohort under study.

EXPERIMENTAL DESIGN

We used data from 5 European and 3 US cohorts of men undergoing biopsy for prostate cancer; six were population-based studies and two were clinical cohorts. The association between PSA and prostate cancer was calculated separately for each cohort using locally-weighted scatterplot smoothing.

RESULTS

The final data set included 25,772 biopsies and 8,503 cancers. There were gross disparities between cohorts with respect to both the prostate cancer risk at a given PSA level and the shape of the risk curve. These disparities were associated with identifiable differences between cohorts: for a given PSA level, a greater number of biopsy cores increased risk of cancer (odds ratio for >6 vs. 6 core biopsy 1.35; 95% C.I. 1.18, 1.54; p<0.0005); recent screening led to a smaller increase in risk per unit change in PSA (p=0.001 for interaction term) and US cohorts had higher risk than the European cohorts (2.14; 95% C.I. 1.99, 2.30; p<0.0005).

CONCLUSIONS

Our results suggest that the relationship between PSA and risk of a positive prostate biopsy varies, both in terms of the probability of prostate cancer at a given PSA value and the shape of the risk curve. This poses challenges to the use of PSA-driven algorithms to determine whether biopsy is indicated.

Background

Risk models to predict prostate cancer on biopsy, whether they include only prostate-specific antigen (PSA) or other markers, are intended for use in all men of screening age. Yet the association between PSA and cancer likely depends on a man’s recent screening history.

Methods

To examine the effect of prior screening on prostate cancer risk prediction using a previously reported four-kallikrein panel: total, free, and intact PSA, and kallikrein-related peptidase 2 (hK2). The study cohort comprised 1241 men in Gothenburg, Sweden, undergoing biopsy for elevated PSA during their second or later visit for the European Randomized study of Screening for Prostate Cancer. We calculated the predictive accuracy of a four-kallikrein panel.

Results

Total PSA was not predictive of prostate cancer. A previously published four-kallikrein model increased predictive accuracy compared to total PSA and age alone (area-under-the-curve [AUC] 0.66 vs. 0.51; p<0.001), but was poorly calibrated and missed many cancers. A model developed with recently screened men gave important improvements in discrimination (AUC 0.67 vs. 0.56; p<0.001). Use of this model would reduce the number of biopsies by 413 per 1000 men with elevated PSA, miss 60 of 216 low-grade (Gleason ≤6) cancers, but miss only 1 of 43 high-grade cancers.

Conclusions

Prior participation in PSA-screening dramatically changes the performance of statistical models predicting biopsy outcome. A four-kallikrein panel can predict prostate cancer in men with a recent screening history, providing independent replication that multiple kallikrein-forms contribute important diagnostic value in men with elevated PSA.

Background

It has been suggested that changes in prostate-specific antigen (PSA) over time (ie, PSA velocity [PSAV]) aid prostate cancer detection. Some guidelines do incorporate PSAV cut points as an indication for biopsy.

Objective

To evaluate whether PSAV enhances prediction of biopsy outcome in a large, representative, population-based cohort.

Design, setting, and participants

There were 2742 screening-arm participants with PSA <3 ng/ml at initial screening in the European Randomized Study of Screening for Prostate Cancer in Rotterdam, Netherlands, or Göteborg, Sweden, and who were subsequently biopsied during rounds 2[en]6 due to elevated PSA.

Measurements

Total, free, and intact PSA and human kallikrein 2 were measured for 1[en]6 screening rounds at intervals of 2 or 4 yr. We created logistic regression models to predict prostate cancer based on age and PSA, with or without free-to-total PSA ratio (%fPSA). PSAV was added to each model and any enhancement in predictive accuracy assessed by area under the curve (AUC).

Results and limitations

PSAV led to small enhancements in predictive accuracy (AUC of 0.569 vs 0.531; 0.626 vs 0.609 if %fPSA was included), although not for high-grade disease. The enhancement depended on modeling a nonlinear relationship between PSAV and cancer. There was no benefit if we excluded men with higher velocities, which were associated with lower risk. These results apply to men in a screening program with elevated PSA; men with prior negative biopsy were not evaluated in this study.

Conclusions

In men with PSA of about ≥3 ng/ml, we found little justification for formal calculation of PSAV or for use of PSAV cut points to determine biopsy. Informal assessment of PSAV will likely aid clinical judgment, such as a sudden rise in PSA suggesting prostatitis, which could be further evaluated before biopsy.

Background

Treatment for localized prostate cancer remains controversial. To our knowledge, there are no outcome studies from contemporary population-based cohorts that include data on stage, Gleason score, and serum levels of prostate-specific antigen (PSA).

Methods

In the National Prostate Cancer Register of Sweden Follow-up Study, a nationwide cohort, we identified 6849 patients aged 70 years or younger. Inclusion criteria were diagnosis with local clinical stage T1–2 prostate cancer from January 1, 1997, through December 31, 2002, a Gleason score of 7 or less, a serum PSA level of less than 20 ng/mL, and treatment with surveillance (including active surveillance and watchful waiting, n = 2021) or curative intent (including radical prostatectomy, n = 3399, and radiation therapy, n = 1429). Among the 6849 patients, 2686 had low-risk prostate cancer (ie, clinical stage T1, Gleason score 2-6, and serum PSA level of <10 ng/mL). The study cohort was linked to the Cause of Death Register, and cumulative incidence of death from prostate cancer and competing causes was calculated.

Results

For the combination of low- and intermediate-risk prostate cancers, calculated cumulative 10-year prostate cancer–specific mortality was 3.6% (95% confidence interval [CI] = 2.7% to 4.8%) in the surveillance group and 2.7% (95% CI = 2.1% to 3.45) in the curative intent group. For those with low-risk disease, the corresponding values were 2.4% (95% CI = 1.2% to 4.1%) among the 1085 patients in the surveillance group and 0.7% (95% CI = 0.3% to 1.4%) among the 1601 patients in the curative intent group. The 10-year risk of dying from competing causes was 19.2% (95% CI = 17.2% to 21.3%) in the surveillance group and 10.2% (95% CI = 9.0% to 11.4%) in the curative intent group.

Conclusion

A 10-year prostate cancer–specific mortality of 2.4% among patients with low-risk prostate cancer in the surveillance group indicates that surveillance may be a suitable treatment option for many patients with low-risk disease.

Background. Prostate-specific antigen (PSA) occurs in different molecular forms in serum: free PSA (fPSA) and complexed PSA (cPSA), the sum of which corresponds to total PSA (tPSA). In addition to tPSA, percent fPSA is widely used in the detection of prostate cancer. Free PSA, ∼28 kDa, is eliminated by glomerular filtration. Previous data showed that men with end-stage renal dysfunction requiring chronic dialysis have increased percent fPSA. In this study, we evaluated whether moderate-to-severe chronic renal dysfunction, but with no need for dialysis, also importantly affects percent fPSA.

Methods. The study group consisted of 101 men (median age 57 years, interquartile range 46–68) with chronic kidney disease and no diagnosis of prostate cancer. Their median glomerular filtration rate (GFR) was 23 mL/min/1.73 m2 (interquartile range 16–33; range 8–83), determined by iohexol clearance. Controls included 5264 men (median age 57 years, interquartile range 54–62) attending a prostate cancer screening program with no diagnosis of prostate cancer during 8 years of follow-up.

Results. With adjustment for age, median fPSA levels and percent fPSA were significantly higher (P < 0.001) in patients with renal dysfunction, 0.45 μg/L and 47.2%, respectively, compared to controls, 0.29 μg/L and 29.9%, respectively. Regression analysis in the study group showed a significant association between GFR and percent fPSA (P = 0.036).

Conclusions. The percent fPSA is importantly influenced by moderately impaired renal function in men with chronic kidney disease. For such men, use of the current clinical decision limits for percent fPSA could cause some men with prostate cancer to be misdiagnosed as having benign disease, and therefore fPSA should not be used to diagnose prostate cancer in these patients.

Background

Prostate-specific antigen (PSA) is widely used to detect prostate cancer. The low positive predictive value of elevated PSA results in large numbers of unnecessary prostate biopsies. We set out to determine whether a multivariable model including four kallikrein forms (total, free, and intact PSA, and human kallikrein 2 (hK2)) could predict prostate biopsy outcome in previously unscreened men with elevated total PSA.

Methods

The study cohort comprised 740 men in Göteborg, Sweden, undergoing biopsy during the first round of the European Randomized study of Screening for Prostate Cancer. We calculated the area-under-the-curve (AUC) for predicting prostate cancer at biopsy. AUCs for a model including age and PSA (the 'laboratory' model) and age, PSA and digital rectal exam (the 'clinical' model) were compared with those for models that also included additional kallikreins.

Results

Addition of free and intact PSA and hK2 improved AUC from 0.68 to 0.83 and from 0.72 to 0.84, for the laboratory and clinical models respectively. Using a 20% risk of prostate cancer as the threshold for biopsy would have reduced the number of biopsies by 424 (57%) and missed only 31 out of 152 low-grade and 3 out of 40 high-grade cancers.

Conclusion

Multiple kallikrein forms measured in blood can predict the result of biopsy in previously unscreened men with elevated PSA. A multivariable model can determine which men should be advised to undergo biopsy and which might be advised to continue screening, but defer biopsy until there was stronger evidence of malignancy.

BACKGROUND

The degree of variability in prostate-specific antigen (PSA) measurements is important for interpreting test results in screening programs, and particularly for interpreting the significance of changes between repeated tests. This study aimed to determine the long-term intra-individual variation for PSA in healthy men.

METHODS

A randomly selected cohort of men in a biennial prostate cancer screening program (ERSPC) conducted in Sweden from 1995–1996 to 2001–2002. We studied men who had total PSA (tPSA) levels <2.0 ng/ml in 2001–2002. This included 791 men with tPSA ≤ 0.61 ng/ml (group A), 1,542 men with tPSA ≤ 0.99 ng/ml (group B), and 1,029 men with tPSA 1.00–1.99 ng/ml (group C). The intra-individual variability of free PSA (fPSA) and tPSA was assessed by calculating coefficients of variation (CV) for each individual’s PSA measurements from the first and second round of screening (1995–1996 and 1997–1998).

RESULTS

Intra-individual CV (geometric means) for tPSA were 13.7%, 12.7%, and 11.5% in groups A, B, and C, respectively. Corresponding CVs for fPSA were significantly lower, ranging from 12.1% to 10.4%. The estimated biological variation of tPSA and fPSA in groups A to C were 12.5%, 11.4%, 10.0% and 9.7%, 7.8%, 7.5%, respectively.

CONCLUSIONS

In healthy men with PSA levels less than 2 ng/ml, the natural long-term variability for tPSA was less than 14%, and with 95% probability, a change in tPSA greater than 30% indicates a change beyond normal random variation.

Background

The aim of the present study was to evaluate the future cumulative risk of prostate cancer in relation to levels of prostate-specific antigen (PSA) in blood and to determine whether this information could be used to individualize the PSA testing interval.

Methods

The study included 5855 of 9972 men (aged 50–66 years) who accepted an invitation to participate in a prospective, randomized study of early detection for prostate cancer. We used a protocol based on biennial PSA measurements starting from 1995 and 1996. Men with serum PSA levels of 3.0 ng/mL or more were offered prostate biopsies.

Results

Among the 5855 men, 539 cases of prostate cancer (9.2%) were detected after a median follow-up of 7.6 years (up to July 1, 2003). Cancer detection rates during the follow-up period in relation to PSA levels were as follows: 0 to 0.49 ng/mL, 0% (0/958); 0.50 to 0.99 ng/mL, 0.9% (17/1992); 1.00 to 1.49 ng/mL, 4.7% (54/1138); 1.50 to 1.99 ng/mL, 12.3% (70/571); 2.00 to 2.49 ng/mL, 21.4% (67/313); 2.50 to 2.99 ng/mL, 25.2% (56/222); 3.00 to 3.99 ng/mL, 33.3% (89/267); 4.00 to 6.99 ng/mL, 38.9% (103/265); 7.00 to 9.99 ng/mL, 50.0% (30/60); and for men with an initial PSA of 10.00 ng/mL or higher, 76.8% (53/69). Not a single case of prostate cancer was detected within 3 years in 2950 men (50.4% of the screened population) with an initial PSA level less than 1 ng/mL.

Conclusions

Retesting intervals should be individualized on the basis of the PSA level, and the large group of men with PSA levels of less than 1 ng/mL can safely be scheduled for a 3-year testing interval.