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Patient selection for prostate biopsy: Risk-based or PSA-based?
British Journal of Medical and Surgical Urology (2012) 5, 128—133
ORIGINAL ARTICLE
Patient selection for prostate biopsy: Risk-based or PSA-based? J. Nariculam a,∗, M. Shabbir a, Karen Thomas b, P.J. Le Roux a, R.M. Walker a, C.R. Charig a, C. Parker a,c a
Epsom and St Helier NHS Trust, Department of Urology, United Kingdom Department of Medical Statistics, Royal Marsden Hospital, United Kingdom c Royal Marsden and Institute of Cancer Research, United Kingdom b
Received 4 June 2011; accepted 20 August 2011
KEYWORDS Prostate cancer; Biopsy; Nomogram; PSA
Summary Aim: The AUA Best Practice Statement on PSA advocates a risk-based approach to selecting men for biopsy, based not on a PSA threshold, but on the risk of finding cancer on biopsy. We have therefore studied the association between candidate risk factors and prostate biopsy results. Method: All patients who underwent a prostate biopsy within the Epsom and St Helier NHS Trust between July 2005 and July 2007 were identified. Those with a serum PSA value of <15.0 ng/ml were selected for inclusion. Univariate and multivariate logistic regression analysis was done to analyse risk factors for the presence of cancer, and of significant cancer, on biopsy. Significant prostate cancer on biopsy was arbitrarily defined as either a Gleason score of 7 or more, or the presence of cancer in 50% or more of the cores. Results: Of 400 cases, 153 (38%) were found to have prostate cancer on biopsy, of which 93 were classed as significant. On multivariate analysis, smaller prostate volume, abnormal DRE, PSA level and absence of previous negative biopsy were independent predictors of significant prostate cancer. The multivariate logistic regression results were used to create a predictive nomogram for significant cancer. Conclusion: The PSA level is merely one of several factors that predict biopsy results. A risk-based, rather than a PSA-based, approach to selecting men for prostate biopsy has the potential to both reduce the number of men undergoing biopsy, and increase the detection of significant cancers. © 2011 British Association of Urological Surgeons. Published by Elsevier Ltd. All rights reserved.
∗
Corresponding author at: Flat 3, Lodden lodge, 10 Devonshire Avenue, Sutton, Surrey SM2 5JL, United Kingdom. Tel.: +44 07958585511. E-mail address: [email protected] (J. Nariculam). 1875-9742/$ — see front matter © 2011 British Association of Urological Surgeons. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bjmsu.2011.08.004
Patient selection for prostate biopsy: Risk-based or PSA-based?
Introduction Until recently, it was widely recommended that all men with a serum PSA elevated above a threshold level should have a prostate biopsy. In 2000, the American Urological Association (AUA) recommended a PSA cut off value of 4.0 ng/ml, above which prostate biopsy should be considered [1]. More recently, the use of such PSA thresholds has been questioned. The Prostate Cancer Prevention Trial (PCPT) showed that 15% of men with a PSA below the previously considered ‘normal’ level had prostate cancer on biopsy [2]. They concluded that there was a ‘continuum of risk’ of prostate cancer, with higher values associated with a greater risk of finding cancer. The likelihood of detecting prostate cancer was not only associated with the PSA level, but also with DRE findings, age, ethnicity, and history of previous negative biopsy. The association between these, and other, risk factors and the presence of cancer on biopsy have been confirmed in other studies [3—6]. In the light of these studies, the 2009 update of the AUA Best Practice Statement on PSA advocates a risk-based approach to selecting men for biopsy, based not on a PSA threshold, but on the risk of finding cancer on biopsy [7]. In the UK it remains common practice to use a PSA threshold to select men for biopsy [8]. To our knowledge, it remains uncertain whether the risk factors for prostate cancer on biopsy identified in North American and European cohorts are also applicable to UK patients. We performed a retrospective analysis of patients undergoing prostate biopsy in our own institution in order to study the association between candidate risk factors and prostate biopsy results.
Methods All patients who underwent a prostate biopsy within the Epsom and St Helier NHS Trust between July 2005 and July 2007 were identified. Those with a serum PSA value of <15.0 ng/ml were selected for inclusion in this study. Patients selected for biopsy had a serum PSA > 4 ng/ml or an abnormal DRE in accordance with routine local clinical practice. All patients underwent transrectal ultrasound guided prostate biopsy, by one of four operators, with between 6 and 12 needle core biopsies taken from each patient. Biopsies were reported by one of four pathologists. Candidate risk factors retrospectively collected from the case records included; presence or absence of lower urinary tract symptoms;
129
patient age; digital rectal examination findings; family history of prostate cancer; previous negative biopsy; most recent serum PSA value prior to biopsy; prostate volume on TRUS according to the prolate ellipsoid formula; histological diagnosis, Gleason sum score, and the number of positive cores.
Statistical methods Univariate and multivariate logistic regression analysis were used to analyse risk factors for the presence of cancer, and of ‘significant cancer’, on biopsy. While there is currently no universally accepted definition of clinically significant prostate cancer, in this study we defined it as a Gleason score of 7 or more, or the presence of cancer in 50% or more of the cores. Candidate risk factors were patient age, PSA level, prostate volume (all as continuous variables), family history (yes/no), previous negative biopsy (yes/no), digital rectal examination (DRE) findings (normal/abnormal), and presence of lower urinary tract symptoms (yes/no). The multivariate logistic regression results were used to create a predictive nomogram for significant cancer according to the method used by Nam et al. [5]. Coefficients from the multivariate analysis were converted into a 1—100 scale. The variable with the greatest difference between levels (prostate volume, with a coefficient equivalent to −5.24 for the maximum observed volume of 162 ml, and −0.4 for the minimum observed volume of 12.7 ml) was converted to 0 points for a volume of 162 ml and 100 points for a volume of 12.7 ml. All other coefficients were converted to points using the same scale. The total points for each observed combination of coefficients were then plotted against the probability of significant cancer, calculated using the logistic regression analysis.
Results Patient characteristics Between July 2005 and July 2007, 568 men had prostate biopsy within the Epsom and St Helier NHS Trust. Of these, 420 had a PSA of less than 15 ng/ml, of whom clinical records were available in 400 cases. These 400 cases formed the study population, and had a median age of 67 years (range 41—83 years), and median PSA 7.65 ng/ml (range 0.3—15.0 ng/ml). The clinical characteristics are shown in Table 1.
130 Table 1
J. Nariculam et al. Patient characteristics.
Characteristics
Number
Number of patients Age (years)
400 41 67 83 203 197 296 104 34 366 48 352 0.3 7.65 15 12.7 49 162
LUTS Digital Rectal Exam Family history Previous prostate biopsy Serum PSA (ng/ml)
Prostate volume (ml)
Min Median Max Yes No Normal Abnormal Yes No Yes No Min Median Max Min Median Max
Biopsy results Of the 400 cases, 153 (38%) were found to have prostate cancer on biopsy. Of the 153 cancers, 83 (54%) had a Gleason score 7—10, 52 (34%) had ≥50% of cores involved, including 10 cases with Gleason 6 disease. Thus, 93 cases (61% of the cancers, or 23% of all patients biopsied) were classed as significant by virtue of either Gleason score 7—10 or ≥50% positive cores. The positive biopsy results are summarised in Table 2.
Risk factors for presence of any cancer on biopsy On univariate analysis, factors associated with the presence of cancer on biopsy were smaller prostate volume, abnormal DRE, older age, higher PSA, the absence of LUTS, positive family history but not previous negative biopsy (see Table 3). On multivariate analysis all but family history remained statistically significant (Table 4). ROC curve for sensitivity/specificity of predicted probability of any cancer, calculated using the multivariate logistic regression model with age, DRE results, LUTS, PSA and prostate volume yielded an AUC of 0.75 (95% CI: 0.70—0.80).
Risk factors for presence of significant cancer on biopsy On univariate analysis, factors associated with the presence of significant cancer on biopsy
%
51 49 74 26 9 91 12 88
were smaller prostate volume, abnormal DRE, higher PSA, older age, previous negative biopsy but not LUTS, or positive family history (see Table 5). On multivariate analysis, prostate volume, DRE, PSA and previous negative biopsy remained statistically significant. ROC curve analysis for sensitivity/specificity of predicted probability of significant cancer, calculated using the multivariate logistic regression model with PSA, prostate volume, DRE and previous negative biopsy yielded an AUC of 0.77 (95% CI: 0.71—0.83). Figure 1 shows the nomogram for risk of significant cancer on biopsy, derived from the above multivariate model (Table 6).
Discussion We have confirmed in a UK cohort that the risk of cancer on biopsy is associated with smaller prostate volume, abnormal DRE, older age, higher PSA, and the absence of LUTS. Given the multiplicity of risk factors, these results support the case for riskbased, rather than PSA-based, selection of men for prostate biopsy. In particular, the data illustrate the importance of prostate volume in predicting biopsy results. Patients with a prostate volume smaller than the median were twice as likely to have significant cancer on biopsy than those with a gland volume greater than the median (30% vs 14%, respectively). Over the past 15 years we have got used to the idea that a man with a raised PSA level should have
Patient selection for prostate biopsy: Risk-based or PSA-based? Table 2
Description of prostate cancer diagnosed on biopsy.
Cancer found on biopsy
Composite Gleason score
Total
Table 3
131
% of cores positive
6 7 8 9 10
Total
<50%
50—75%
≥75%
60 29 5 7 0 101
8 14 1 1 0 24
2 17 2 6 1 28
70 60 8 14 1 153
Univariate analysis for presence of any cancer.
Variable
Odds ratio (95% CI)
p-value
Prostate volume (unit increase) DRE Normal Abnormal Age (1-year increase) PSA (1 ng/ml increase) LUTS No Yes Family history No Yes Previous biopsy No Yes
0.979 (0.969, 0.988)
<0.001
1 2.817 (1.781, 4.457) 1.066 (1.034, 1.099) 1.101 (1.027, 1.180)
<0.001 <0.001 0.007
1 0.636 (0.424, 0.954)
0.029
1 2.193 (1.079, 4.459)
0.030
0.785 (0.415, 1.484)
0.456
a prostate biopsy. Around 80,000 prostate biopsies are performed in the UK each year, of which around 50,000 are negative. We should make it a priority to find safe ways of reducing this huge number of ‘unnecessary’ biopsies. It is possible that a riskbased, rather than a PSA-based approach would help in this regard. Using a risk-based approach, it would be possible to identify men who, although they had a raised PSA level, were at low risk of significant cancer, and could therefore avoid biopsy. All the patients in this study were used to produce
Table 4
the predictive nomogram leaving none for a validation set so this model has not been internally validated, and has yet to be externally validated. However, despite this important limitation, the nomogram can be used to illustrate the way in which a risk-based approach could be used. Of the 400 men in the study, the nomogram identifies 43 (11%) who had a risk of significant cancer of ≤5%. If these men had not been biopsied, just 1/93 (1.1%) significant cancers would have been missed. One other limitation of this study was that there was no
Multivariate analysis for presence of any cancer.
Prostate volume (unit increase) DRE Normal Abnormal Age (1-year increase) PSA (1 ng/ml increase) LUTS No Yes
Odds ratio (95% CI)
p-value
0.975 (0.965, 0.986)
<0.001
1 2.651 (1.553, 4.525) 1.057 (1.020, 1.095) 1.111 (1.023, 1.207)
<0.001 0.002 0.013
1 0.587 (0.362, 0.953)
0.031
132
J. Nariculam et al.
Table 5
Univariate analysis for presence of significant cancer on biopsy.
Variable Prostate volume (unit increase) DRE Normal Abnormal PSA (1 ng/ml increase) Age (1-year increase) Previous biopsy No Yes LUTS No Yes Family history No Yes a
Odds ratio (95% CI)
p-valuea
352
0.971 (0.958, 0.984)
<0.001
296 104 400 400
2.866 (1.748, 4.698) 1.158 (1.069, 1.255) 1.058 (1.022, 1.096)
<0.001 <0.001 0.001
352 48
0.269 (0.094, 0.769)
0.014
197 203
0.706 (0.443, 1.125)
0.143
366 34
1.919 (0.911, 4.044)
0.087
N
Logistic regression.
complete data for the analysis of whether ethnicity was associated with predicting significant cancer on biopsy. A risk-based approach could, not only help to avoid unnecessary biopsies, but also identify significant cancers in men with a ‘‘normal’’ PSA level, who would not normally be selected for biopsy. For example, a man with a PSA level of 2 ng/ml, a gland volume of 20 ml, a normal DRE and no previous negative biopsy would have a predicted risk of significant cancer on biopsy of 20% according to the nomogram. If the nomogram were validated, notwithstanding his low PSA level, he would be well advised to have a prostate biopsy. Our findings are consistent with previous studies from North America. For example, Nam et al. retrospectively analysed the biopsy results of 2637 men who underwent TRUS biopsy on account of an elevated PSA and/or abnormal DRE. They observed that age, ethnicity, family history, previous
Table 6
negative biopsy and prostate volume were all predictive for cancer [4]. In a subsequent update of this study, using data from 3108 men, they made a predictive model using age, family history, ethnicity, urinary symptoms, PSA, free:total PSA ratio, and digital rectal examination [5]. They used free:total PSA, rather than prostate volume, having observed a close correlation between these two variables, and given that free:total PSA is much more readily obtained. Interestingly, the AUC for their nomogram in predicting high grade cancer was 0.77, remarkably similar to our data. Vickers et al. have reported a decision analysis to illustrate the effect of using a risk-based, rather than a PSA-based, approach [9]. Based on data from 740 men who underwent prostate biopsy for an elevated PSA, they developed a nomogram involving 4 kallikrein forms (total, free and intact PSA and human kallikrein 2) to predict prostate biopsy outcome. They found that if one were to use a 20% risk
Multivariate analysis for presence of significant cancer on biopsy. N
Variables included in the model Prostate volume (unit increase) DRE Normal Abnormal PSA (1 ng/ml increase) Previous biopsy No Yes
352
Odds ratio (95% CI)
p-value
0.968 (0.955, 0.982)
<0.001
1 2.816 (1.581, 5.016) 1.224 (1.116, 1.341)
<0.001 <0.001
1 0.219 (0.063, 0.762)
0.017
Patient selection for prostate biopsy: Risk-based or PSA-based?
133
validate the existing predictive nomograms in UK series, with a view to widespread implementation.
Nomogram for predicting significant prostate cancer on biopsy Volume 162 150
125
100
75
50
25 12.7
Acknowledgements
PSA 0
3
6
9
12
15
DRE Normal
Abnormal
Previous biopsy Yes
No
0.0
20.0
40.0
60.0
80.0
100.0
120.0
Points
Probability of diagnosing significant prostate cancer on biopsy
90% 80% 70%
Part of this work was undertaken in The Royal Marsden NHS Foundation Trust who received a proportion of its funding from the NHS Executive; the views expressed in this publication are those of the authors and not necessarily those of the NHS Executive. This work was supported by the Institute of Cancer Research, the Cancer Research UK Section of Radiotherapy [CRUK], grant number C46/A3970 and NCRI South of England Prostate Cancer Collaborative. We acknowledge NHS funding to the NIHR Biochemical Research Centre.
60% 50%
References
40% 30% 20% 10% 0% 50
70
90
110
130
150
170
190
210
Points
Figure 1 A nomogram for predicting significant prostate cancer on biopsy.
for prostate cancer as the indication for biopsy, the number of men undergoing biopsy would be reduced by 57%, while missing only 3 of 40 high grade cancers.
Summary The decision whether or not to have a prostate biopsy should be based on the risk of finding a cancer that needs treatment. We have confirmed the findings from the US studies that the PSA level is just one of several factors that predict biopsy results, and that other factors, such as prostate volume, DRE findings and previous negative biopsy, are just as important. A risk-based, rather than a PSA-based, approach to selecting men for prostate biopsy has the potential to both reduce the number of men undergoing biopsy and to increase the yield of significant cancers. Future work should seek to
[1] American Urological Association (AUA). Prostate-specific antigen (PSA) best practice policy. Oncology (Williston Park) 2000;14:267—72, 277—8, 280. [2] Thompson IM, Ankerst DP, Chi C, Goodman PJ, Tangen CM, Lucia MS, et al. Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst 2006;98(April (8)):529—34. [3] Van den Bergh RC, Roobol MJ, Wolters T, van Leeuwen PJ, Schröder FH. The Prostate Cancer Prevention Trial and European Randomized Study of Screening for Prostate Cancer risk calculators indicating a positive prostate biopsy: a comparison. BJU Int 2008;102(November (9)):1068—73. [4] Nam RK, Toi A, Trachtenberg J, Klotz LH, Jewett MAS, Emami M, et al. Making sense of prostate specific antigen: improving its predictive value in patients undergoing prostate biopsy. J Urol 2006;175(February (2)):489—94. [5] Nam RK, Toi A, Klotz LH, Trachtenberg J, Jewett MAS, Appu S, et al. Assessing individual risk for prostate cancer. J Clin Oncol 2007;August (25)(24):3582—8. [6] Nam RK, Toi A, Klotz LH, Trachtenberg J, Jewett MA, Loblaw A, et al. Nomogram prediction for prostate cancer and aggressive prostate cancer at time of biopsy: utilizing all risk factors and tumor markers for prostate cancer. Can J Urol 2006;13(April (Suppl. 2)):2—10. [7] AUA. http://www.auanet.org/content/guidelines-andquality-care/clinical-guidelines/main-reports/psa09.pdf. [8] UK NHS. http://www.cancerscreening. nhs.uk/prostate/prostate-patient-infosheet pdf [accessed May 2007]. [9] Vickers AJ, Cronin AM, Aus G, Pihl C-G, Becker C, Pettersson K, et al. A panel of kallikrein markers can reduce unnecessary biopsy for prostate cancer: data from the European Randomized Study of Prostate Cancer Screening in Göteborg, Sweden. BMC Med 2008;6:19.
Available online at www.sciencedirect.com
ORIGINAL ARTICLE
Patient selection for prostate biopsy: Risk-based or PSA-based? J. Nariculam a,∗, M. Shabbir a, Karen Thomas b, P.J. Le Roux a, R.M. Walker a, C.R. Charig a, C. Parker a,c a
Epsom and St Helier NHS Trust, Department of Urology, United Kingdom Department of Medical Statistics, Royal Marsden Hospital, United Kingdom c Royal Marsden and Institute of Cancer Research, United Kingdom b
Received 4 June 2011; accepted 20 August 2011
KEYWORDS Prostate cancer; Biopsy; Nomogram; PSA
Summary Aim: The AUA Best Practice Statement on PSA advocates a risk-based approach to selecting men for biopsy, based not on a PSA threshold, but on the risk of finding cancer on biopsy. We have therefore studied the association between candidate risk factors and prostate biopsy results. Method: All patients who underwent a prostate biopsy within the Epsom and St Helier NHS Trust between July 2005 and July 2007 were identified. Those with a serum PSA value of <15.0 ng/ml were selected for inclusion. Univariate and multivariate logistic regression analysis was done to analyse risk factors for the presence of cancer, and of significant cancer, on biopsy. Significant prostate cancer on biopsy was arbitrarily defined as either a Gleason score of 7 or more, or the presence of cancer in 50% or more of the cores. Results: Of 400 cases, 153 (38%) were found to have prostate cancer on biopsy, of which 93 were classed as significant. On multivariate analysis, smaller prostate volume, abnormal DRE, PSA level and absence of previous negative biopsy were independent predictors of significant prostate cancer. The multivariate logistic regression results were used to create a predictive nomogram for significant cancer. Conclusion: The PSA level is merely one of several factors that predict biopsy results. A risk-based, rather than a PSA-based, approach to selecting men for prostate biopsy has the potential to both reduce the number of men undergoing biopsy, and increase the detection of significant cancers. © 2011 British Association of Urological Surgeons. Published by Elsevier Ltd. All rights reserved.
∗
Corresponding author at: Flat 3, Lodden lodge, 10 Devonshire Avenue, Sutton, Surrey SM2 5JL, United Kingdom. Tel.: +44 07958585511. E-mail address: [email protected] (J. Nariculam). 1875-9742/$ — see front matter © 2011 British Association of Urological Surgeons. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bjmsu.2011.08.004
Patient selection for prostate biopsy: Risk-based or PSA-based?
Introduction Until recently, it was widely recommended that all men with a serum PSA elevated above a threshold level should have a prostate biopsy. In 2000, the American Urological Association (AUA) recommended a PSA cut off value of 4.0 ng/ml, above which prostate biopsy should be considered [1]. More recently, the use of such PSA thresholds has been questioned. The Prostate Cancer Prevention Trial (PCPT) showed that 15% of men with a PSA below the previously considered ‘normal’ level had prostate cancer on biopsy [2]. They concluded that there was a ‘continuum of risk’ of prostate cancer, with higher values associated with a greater risk of finding cancer. The likelihood of detecting prostate cancer was not only associated with the PSA level, but also with DRE findings, age, ethnicity, and history of previous negative biopsy. The association between these, and other, risk factors and the presence of cancer on biopsy have been confirmed in other studies [3—6]. In the light of these studies, the 2009 update of the AUA Best Practice Statement on PSA advocates a risk-based approach to selecting men for biopsy, based not on a PSA threshold, but on the risk of finding cancer on biopsy [7]. In the UK it remains common practice to use a PSA threshold to select men for biopsy [8]. To our knowledge, it remains uncertain whether the risk factors for prostate cancer on biopsy identified in North American and European cohorts are also applicable to UK patients. We performed a retrospective analysis of patients undergoing prostate biopsy in our own institution in order to study the association between candidate risk factors and prostate biopsy results.
Methods All patients who underwent a prostate biopsy within the Epsom and St Helier NHS Trust between July 2005 and July 2007 were identified. Those with a serum PSA value of <15.0 ng/ml were selected for inclusion in this study. Patients selected for biopsy had a serum PSA > 4 ng/ml or an abnormal DRE in accordance with routine local clinical practice. All patients underwent transrectal ultrasound guided prostate biopsy, by one of four operators, with between 6 and 12 needle core biopsies taken from each patient. Biopsies were reported by one of four pathologists. Candidate risk factors retrospectively collected from the case records included; presence or absence of lower urinary tract symptoms;
129
patient age; digital rectal examination findings; family history of prostate cancer; previous negative biopsy; most recent serum PSA value prior to biopsy; prostate volume on TRUS according to the prolate ellipsoid formula; histological diagnosis, Gleason sum score, and the number of positive cores.
Statistical methods Univariate and multivariate logistic regression analysis were used to analyse risk factors for the presence of cancer, and of ‘significant cancer’, on biopsy. While there is currently no universally accepted definition of clinically significant prostate cancer, in this study we defined it as a Gleason score of 7 or more, or the presence of cancer in 50% or more of the cores. Candidate risk factors were patient age, PSA level, prostate volume (all as continuous variables), family history (yes/no), previous negative biopsy (yes/no), digital rectal examination (DRE) findings (normal/abnormal), and presence of lower urinary tract symptoms (yes/no). The multivariate logistic regression results were used to create a predictive nomogram for significant cancer according to the method used by Nam et al. [5]. Coefficients from the multivariate analysis were converted into a 1—100 scale. The variable with the greatest difference between levels (prostate volume, with a coefficient equivalent to −5.24 for the maximum observed volume of 162 ml, and −0.4 for the minimum observed volume of 12.7 ml) was converted to 0 points for a volume of 162 ml and 100 points for a volume of 12.7 ml. All other coefficients were converted to points using the same scale. The total points for each observed combination of coefficients were then plotted against the probability of significant cancer, calculated using the logistic regression analysis.
Results Patient characteristics Between July 2005 and July 2007, 568 men had prostate biopsy within the Epsom and St Helier NHS Trust. Of these, 420 had a PSA of less than 15 ng/ml, of whom clinical records were available in 400 cases. These 400 cases formed the study population, and had a median age of 67 years (range 41—83 years), and median PSA 7.65 ng/ml (range 0.3—15.0 ng/ml). The clinical characteristics are shown in Table 1.
130 Table 1
J. Nariculam et al. Patient characteristics.
Characteristics
Number
Number of patients Age (years)
400 41 67 83 203 197 296 104 34 366 48 352 0.3 7.65 15 12.7 49 162
LUTS Digital Rectal Exam Family history Previous prostate biopsy Serum PSA (ng/ml)
Prostate volume (ml)
Min Median Max Yes No Normal Abnormal Yes No Yes No Min Median Max Min Median Max
Biopsy results Of the 400 cases, 153 (38%) were found to have prostate cancer on biopsy. Of the 153 cancers, 83 (54%) had a Gleason score 7—10, 52 (34%) had ≥50% of cores involved, including 10 cases with Gleason 6 disease. Thus, 93 cases (61% of the cancers, or 23% of all patients biopsied) were classed as significant by virtue of either Gleason score 7—10 or ≥50% positive cores. The positive biopsy results are summarised in Table 2.
Risk factors for presence of any cancer on biopsy On univariate analysis, factors associated with the presence of cancer on biopsy were smaller prostate volume, abnormal DRE, older age, higher PSA, the absence of LUTS, positive family history but not previous negative biopsy (see Table 3). On multivariate analysis all but family history remained statistically significant (Table 4). ROC curve for sensitivity/specificity of predicted probability of any cancer, calculated using the multivariate logistic regression model with age, DRE results, LUTS, PSA and prostate volume yielded an AUC of 0.75 (95% CI: 0.70—0.80).
Risk factors for presence of significant cancer on biopsy On univariate analysis, factors associated with the presence of significant cancer on biopsy
%
51 49 74 26 9 91 12 88
were smaller prostate volume, abnormal DRE, higher PSA, older age, previous negative biopsy but not LUTS, or positive family history (see Table 5). On multivariate analysis, prostate volume, DRE, PSA and previous negative biopsy remained statistically significant. ROC curve analysis for sensitivity/specificity of predicted probability of significant cancer, calculated using the multivariate logistic regression model with PSA, prostate volume, DRE and previous negative biopsy yielded an AUC of 0.77 (95% CI: 0.71—0.83). Figure 1 shows the nomogram for risk of significant cancer on biopsy, derived from the above multivariate model (Table 6).
Discussion We have confirmed in a UK cohort that the risk of cancer on biopsy is associated with smaller prostate volume, abnormal DRE, older age, higher PSA, and the absence of LUTS. Given the multiplicity of risk factors, these results support the case for riskbased, rather than PSA-based, selection of men for prostate biopsy. In particular, the data illustrate the importance of prostate volume in predicting biopsy results. Patients with a prostate volume smaller than the median were twice as likely to have significant cancer on biopsy than those with a gland volume greater than the median (30% vs 14%, respectively). Over the past 15 years we have got used to the idea that a man with a raised PSA level should have
Patient selection for prostate biopsy: Risk-based or PSA-based? Table 2
Description of prostate cancer diagnosed on biopsy.
Cancer found on biopsy
Composite Gleason score
Total
Table 3
131
% of cores positive
6 7 8 9 10
Total
<50%
50—75%
≥75%
60 29 5 7 0 101
8 14 1 1 0 24
2 17 2 6 1 28
70 60 8 14 1 153
Univariate analysis for presence of any cancer.
Variable
Odds ratio (95% CI)
p-value
Prostate volume (unit increase) DRE Normal Abnormal Age (1-year increase) PSA (1 ng/ml increase) LUTS No Yes Family history No Yes Previous biopsy No Yes
0.979 (0.969, 0.988)
<0.001
1 2.817 (1.781, 4.457) 1.066 (1.034, 1.099) 1.101 (1.027, 1.180)
<0.001 <0.001 0.007
1 0.636 (0.424, 0.954)
0.029
1 2.193 (1.079, 4.459)
0.030
0.785 (0.415, 1.484)
0.456
a prostate biopsy. Around 80,000 prostate biopsies are performed in the UK each year, of which around 50,000 are negative. We should make it a priority to find safe ways of reducing this huge number of ‘unnecessary’ biopsies. It is possible that a riskbased, rather than a PSA-based approach would help in this regard. Using a risk-based approach, it would be possible to identify men who, although they had a raised PSA level, were at low risk of significant cancer, and could therefore avoid biopsy. All the patients in this study were used to produce
Table 4
the predictive nomogram leaving none for a validation set so this model has not been internally validated, and has yet to be externally validated. However, despite this important limitation, the nomogram can be used to illustrate the way in which a risk-based approach could be used. Of the 400 men in the study, the nomogram identifies 43 (11%) who had a risk of significant cancer of ≤5%. If these men had not been biopsied, just 1/93 (1.1%) significant cancers would have been missed. One other limitation of this study was that there was no
Multivariate analysis for presence of any cancer.
Prostate volume (unit increase) DRE Normal Abnormal Age (1-year increase) PSA (1 ng/ml increase) LUTS No Yes
Odds ratio (95% CI)
p-value
0.975 (0.965, 0.986)
<0.001
1 2.651 (1.553, 4.525) 1.057 (1.020, 1.095) 1.111 (1.023, 1.207)
<0.001 0.002 0.013
1 0.587 (0.362, 0.953)
0.031
132
J. Nariculam et al.
Table 5
Univariate analysis for presence of significant cancer on biopsy.
Variable Prostate volume (unit increase) DRE Normal Abnormal PSA (1 ng/ml increase) Age (1-year increase) Previous biopsy No Yes LUTS No Yes Family history No Yes a
Odds ratio (95% CI)
p-valuea
352
0.971 (0.958, 0.984)
<0.001
296 104 400 400
2.866 (1.748, 4.698) 1.158 (1.069, 1.255) 1.058 (1.022, 1.096)
<0.001 <0.001 0.001
352 48
0.269 (0.094, 0.769)
0.014
197 203
0.706 (0.443, 1.125)
0.143
366 34
1.919 (0.911, 4.044)
0.087
N
Logistic regression.
complete data for the analysis of whether ethnicity was associated with predicting significant cancer on biopsy. A risk-based approach could, not only help to avoid unnecessary biopsies, but also identify significant cancers in men with a ‘‘normal’’ PSA level, who would not normally be selected for biopsy. For example, a man with a PSA level of 2 ng/ml, a gland volume of 20 ml, a normal DRE and no previous negative biopsy would have a predicted risk of significant cancer on biopsy of 20% according to the nomogram. If the nomogram were validated, notwithstanding his low PSA level, he would be well advised to have a prostate biopsy. Our findings are consistent with previous studies from North America. For example, Nam et al. retrospectively analysed the biopsy results of 2637 men who underwent TRUS biopsy on account of an elevated PSA and/or abnormal DRE. They observed that age, ethnicity, family history, previous
Table 6
negative biopsy and prostate volume were all predictive for cancer [4]. In a subsequent update of this study, using data from 3108 men, they made a predictive model using age, family history, ethnicity, urinary symptoms, PSA, free:total PSA ratio, and digital rectal examination [5]. They used free:total PSA, rather than prostate volume, having observed a close correlation between these two variables, and given that free:total PSA is much more readily obtained. Interestingly, the AUC for their nomogram in predicting high grade cancer was 0.77, remarkably similar to our data. Vickers et al. have reported a decision analysis to illustrate the effect of using a risk-based, rather than a PSA-based, approach [9]. Based on data from 740 men who underwent prostate biopsy for an elevated PSA, they developed a nomogram involving 4 kallikrein forms (total, free and intact PSA and human kallikrein 2) to predict prostate biopsy outcome. They found that if one were to use a 20% risk
Multivariate analysis for presence of significant cancer on biopsy. N
Variables included in the model Prostate volume (unit increase) DRE Normal Abnormal PSA (1 ng/ml increase) Previous biopsy No Yes
352
Odds ratio (95% CI)
p-value
0.968 (0.955, 0.982)
<0.001
1 2.816 (1.581, 5.016) 1.224 (1.116, 1.341)
<0.001 <0.001
1 0.219 (0.063, 0.762)
0.017
Patient selection for prostate biopsy: Risk-based or PSA-based?
133
validate the existing predictive nomograms in UK series, with a view to widespread implementation.
Nomogram for predicting significant prostate cancer on biopsy Volume 162 150
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50
25 12.7
Acknowledgements
PSA 0
3
6
9
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DRE Normal
Abnormal
Previous biopsy Yes
No
0.0
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Points
Probability of diagnosing significant prostate cancer on biopsy
90% 80% 70%
Part of this work was undertaken in The Royal Marsden NHS Foundation Trust who received a proportion of its funding from the NHS Executive; the views expressed in this publication are those of the authors and not necessarily those of the NHS Executive. This work was supported by the Institute of Cancer Research, the Cancer Research UK Section of Radiotherapy [CRUK], grant number C46/A3970 and NCRI South of England Prostate Cancer Collaborative. We acknowledge NHS funding to the NIHR Biochemical Research Centre.
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References
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Figure 1 A nomogram for predicting significant prostate cancer on biopsy.
for prostate cancer as the indication for biopsy, the number of men undergoing biopsy would be reduced by 57%, while missing only 3 of 40 high grade cancers.
Summary The decision whether or not to have a prostate biopsy should be based on the risk of finding a cancer that needs treatment. We have confirmed the findings from the US studies that the PSA level is just one of several factors that predict biopsy results, and that other factors, such as prostate volume, DRE findings and previous negative biopsy, are just as important. A risk-based, rather than a PSA-based, approach to selecting men for prostate biopsy has the potential to both reduce the number of men undergoing biopsy and to increase the yield of significant cancers. Future work should seek to
[1] American Urological Association (AUA). Prostate-specific antigen (PSA) best practice policy. Oncology (Williston Park) 2000;14:267—72, 277—8, 280. [2] Thompson IM, Ankerst DP, Chi C, Goodman PJ, Tangen CM, Lucia MS, et al. Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst 2006;98(April (8)):529—34. [3] Van den Bergh RC, Roobol MJ, Wolters T, van Leeuwen PJ, Schröder FH. The Prostate Cancer Prevention Trial and European Randomized Study of Screening for Prostate Cancer risk calculators indicating a positive prostate biopsy: a comparison. BJU Int 2008;102(November (9)):1068—73. [4] Nam RK, Toi A, Trachtenberg J, Klotz LH, Jewett MAS, Emami M, et al. Making sense of prostate specific antigen: improving its predictive value in patients undergoing prostate biopsy. J Urol 2006;175(February (2)):489—94. [5] Nam RK, Toi A, Klotz LH, Trachtenberg J, Jewett MAS, Appu S, et al. Assessing individual risk for prostate cancer. J Clin Oncol 2007;August (25)(24):3582—8. [6] Nam RK, Toi A, Klotz LH, Trachtenberg J, Jewett MA, Loblaw A, et al. Nomogram prediction for prostate cancer and aggressive prostate cancer at time of biopsy: utilizing all risk factors and tumor markers for prostate cancer. Can J Urol 2006;13(April (Suppl. 2)):2—10. [7] AUA. http://www.auanet.org/content/guidelines-andquality-care/clinical-guidelines/main-reports/psa09.pdf. [8] UK NHS. http://www.cancerscreening. nhs.uk/prostate/prostate-patient-infosheet pdf [accessed May 2007]. [9] Vickers AJ, Cronin AM, Aus G, Pihl C-G, Becker C, Pettersson K, et al. A panel of kallikrein markers can reduce unnecessary biopsy for prostate cancer: data from the European Randomized Study of Prostate Cancer Screening in Göteborg, Sweden. BMC Med 2008;6:19.
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