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Article of the Week: ERSPC risk calculators significantly outperform the PCPT 2.0 in the prediction of PCa

Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculators significantly outperform the Prostate Cancer Prevention Trial (PCPT) 2.0 in the prediction of prostate cancer: a multi-institutional study

Robert W. Foley*,, Robert M. Maweni, Laura Gorman, Keefe Murphy§,, Dara J. Lundon Z*,,**, Garrett Durkan††,‡‡, Richard Power§§, Frank OBrien¶¶, Kieran J. OMalley**, David J. Galvin,**,***, T. Brendan Murphy§,¶ and R. William Watson*,

 

*UCD School of Medicine, University College Dublin, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland, Croydon NHS Trust, Croydon University Hospital, London, UK, §UCD School of Mathematical Sciences, University College Dublin, Insight Centre for Data Analytics, University College Dublin, **Department of Urology, Mater Misericordiae University Hospital, Dublin, ††Department of Urology, University Hospital Galway, Galway, ‡‡Department of Urology, University Hospital Limerick, Limerick, §§Department of Urology, Beaumont Hospital, Dublin, ¶¶Department of Urology, University Hospital Waterford, Waterford, and ***Department of Urology, St. Vincents University Hospital, Dublin, Ireland

 

Objective

To analyse the performance of the Prostate Cancer Prevention Trial Risk Calculator (PCPT-RC) and two iterations of the European Randomised Study of Screening for Prostate Cancer (ERSPC) Risk Calculator, one of which incorporates prostate volume (ERSPC-RC) and the other of which incorporates prostate volume and the prostate health index (PHI) in a referral population (ERSPC-PHI).

Patients and Methods

The risk of prostate cancer (PCa) and significant PCa (Gleason score ≥7) in 2001 patients from six tertiary referral centres was calculated according to the PCPT-RC and ERSPC-RC formulae. The calculators’ predictions were analysed using the area under the receiver-operating characteristic curve (AUC), calibration plots, Hosmer–Lemeshow test for goodness of fit and decision-curve analysis. In a subset of 222 patients for whom the PHI score was available, each patient’s risk was calculated as per the ERSPC-RC and ERSPC-PHI risk calculators.

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Results

The ERSPC-RC outperformed the PCPT-RC in the prediction of PCa, with an AUC of 0.71 compared with 0.64, and also outperformed the PCPT-RC in the prediction of significant PCa (P<0.001), with an AUC of 0.74 compared with 0.69. The ERSPC-RC was found to have improved calibration in this cohort and was associated with a greater net benefit on decision-curve analysis for both PCa and significant PCa. The performance of the ERSPC-RC was further improved through the addition of the PHI score in a subset of 222 patients. The AUCs of the ERSPC-PHI were 0.76 and 0.78 for PCa and significant PCa prediction, respectively, in comparison with AUC values of 0.72 in the prediction of both PCa and significant PCa for the ERSPC-RC (P = 0.12 and P = 0.04, respectively). The ERSPC-PHI risk calculator was well calibrated in this cohort and had an increase in net benefit over that of the ERSPC-RC.

Conclusions

The performance of the risk calculators in the present cohort shows that the ERSPC-RC is a superior tool in the prediction of PCa; however the performance of the ERSPC-RC in this population does not yet warrant its use in clinical practice. The incorporation of the PHI score into the ERSPC-PHI risk calculator allowed each patient’s risk to be more accurately quantified. Individual patient risk calculation using the ERSPC-PHI risk calculator can be undertaken in order to allow a systematic approach to patient risk stratification and to aid in the diagnosis of PCa.

Editorial: Prostate cancer risk calculators – still much work ahead

Several risk calculators (RCs) have been developed to predict prostate cancer (PCa) diagnosis at prostate biopsy. These multivariable tools have constantly been shown to be superior to risk prediction using PSA testing alone. Their use in personalized clinical decision-making is thus increasingly recommended to reduce overdiagnosis and overtreatment of PCa [1]. Foley et al. [2] conducted a multi-institutional external validation of the most recent versions of the European Randomised Study of Screening for Prostate Cancer Risk Calculator (ERSPC-RC) and the Prostate Cancer Prevention Trial Risk Calculator (PCPT-RC) in a large cohort of patients from six different Irish tertiary referral centres. The study showed that the two RCs performed moderately well. Both RCs performed less optimistic compared with their original reports. The ERSPC-RC showed superior discrimination (area under the curve of 0.74 vs 0.69 for high grade PCa) and a greater net benefit in decision-curve analysis (DCA) than the PCPT-RC; however, although the ERSPC-RC was superior to the PCPT-RC in this well-conducted study, neither RC can be recommended for PCa risk prediction in this specific Irish cohort.

The authors chose to perform DCAs, which are of great value for further assessing the utility of a risk prediction model using visualization of the clinical net benefit and net harm. The benefit threshold of >30%, as shown in the DCA of the ERSPC-RC for high grade PCa, is too high for a clinically meaningful prediction tool. Below this threshold the RC did not provide further benefit compared with a strategy of performing a biopsy on everybody. It is questionable whether clinicians or patients would opt to use an RC which only provides a benefit if a risk of 30% as the lowest acceptable threshold for high grade disease is accepted.

What are the reasons for the suboptimum performance of the RCs in the Irish cohort? It is well known that RC performance is often less optimistic in external validations [3]. Differences in cohort characteristics, biopsy strategies and screening recommendations between RC development cohorts and the tested cohorts, but also changes in clinical practice over time, are potential reasons. Although the RCs have constantly been modified to establish their role as a general one-size-fits-all risk prediction model, their performance varied significantly in different cohorts. We recently evaluated the same RCs in a large Swiss single-centre cohort and found similar discrimination but better calibration, a greater net benefit and a lower and thus clinically useful benefit threshold in DCAs compared with the present Irish study [4]. The cohort in the present study was unique because it consisted of a highly preselected group of patients. This is attributable to the specific referral practice for prostate biopsies in Ireland and is reflected in the high number of patients with a positive DRE (47% in the group diagnosed with PCa) or a positive family history (11%). Accordingly, the overall PCa detection rate (58%) and the detection rate of high grade disease (35%) were higher than usually expected. From a scientific point of view, the Irish cohort is not the optimum cohort to validate these RCs. Far more importantly, however, from a clinical point of view, the evaluation showed that these RCs are not really useful in the specific Irish health system.

What can be done to improve the performance RCs in the future? It is obvious that specific characteristics of the tested cohorts will affect RC performance. These local or regional characteristics usually cannot be changed. Thus modifications of available RCs according to local patient practice might be necessary. This concept has recently been examined by Strobl et al. [5]. They were able to show that recalibration of the static PCPT-RC according to local cohort and practice characteristics can improve its accuracy. Additionally, RCs developed from contemporary clinical cohorts that were, for example, diagnosed using current state-of-the-art biopsy strategies (i.e. 12-core biopsies) instead of historical cohorts from, for example, randomized clinical trials might also result in better RC performance in clinical practice. Furthermore, the inclusion of novel variables in the RC might be useful. Results from imaging studies, such as multiparametric prostate MRI, or promising new biomarkers might increase the overall performance of PCa RCs. The study by Foley et al. shows that the inclusion of novel markers can be of benefit. The ERSPC-PHI RC, which includes the Prostate Health Index (PHI) as an additional variable, was investigated in a subset of patients in their study and was superior to the conventional ERSPC-RC; however, when novel variables are integrated, their potential clinical harm (e.g. unpleasant or costly investigations) has to be balanced against their potential benefit.

The work of Foley et al. nicely illustrates the limitations of current PCa RCs. Locally tailored static RCs, RCs based on contemporary clinical cohorts, or RCs including novel variables need to be developed to assess whether overall RC performance can be improved in the future. There is still much work to do!

Cedric Poyet and Thom as Hermanns 

 

Department of Urology, University Hospital Zurich, University of Zurich, Zurich, Switzerland

 

References

 

 

Article of the Month: ERSPC and PCPT risk calculators in prostate cancer risk prediction

Every Month the Editor-in-Chief selects an Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Prostate cancer risk prediction using the novel versions of the European Randomised Study for Screening of Prostate Cancer (ERSPC) and Prostate Cancer Prevention Trial (PCPT) risk calculators: independent validation and comparison in a contemporary European cohort

Cedric Poyet, Daan Nieboer*, Bimal Bhindi, Girish S. Kulkarni, Caroline WiederkehrMarian S. Wettstein, Remo Largo, Peter Wild, Tullio Sulser and Thomas Hermanns 

 

Department of Urology, University Hospital Zurich, University of Zurich, Zurich, Switzerland, *Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, Division of Urology, Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada, and Institute of Surgical Pathology, University Hospital Zurich, University of Zurich, Zurich, Switzerland

 

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Objectives

To externally validate and compare the two novel versions of the European Randomised Study for Screening of Prostate Cancer (ERSPC)-prostate cancer risk calculator (RC) and Prostate Cancer Prevention Trial (PCPT)-RC.

Patients and Methods

All men who underwent a transrectal prostate biopsy in a European tertiary care centre between 2004 and 2012 were retrospectively identified. The probability of detecting prostate cancer and significant cancer (Gleason score ≥7) was calculated for each man using the novel versions of the ERSPC-RC (DRE-based version 3/4) and the PCPT-RC (version 2.0) and compared with biopsy results. Calibration and discrimination were assessed using the calibration slope method and the area under the receiver operating characteristic curve (AUC), respectively. Additionally, decision curve analyses were performed.

MarchATOM1

Results

Of 1 996 men, 483 (24%) were diagnosed with prostate cancer and 226 (11%) with significant prostate cancer. Calibration of the two RCs was comparable, although the PCPT-RC was slightly superior in the higher risk prediction range for any and significant prostate cancer. Discrimination of the ERSPC- and PCPT-RC was comparable for any prostate cancer (AUCs 0.65 vs 0.66), while the ERSPC-RC was somewhat better for significant prostate cancer (AUCs 0.73 vs 0.70). Decision curve analyses revealed a comparable net benefit for any prostate cancer and a slightly greater net benefit for significant prostate cancer using the ERSPC-RC.

Conclusions

In our independent external validation, both updated RCs showed less optimistic performance compared with their original reports, particularly for the prediction of any prostate cancer. Risk prediction of significant prostate cancer, which is important to avoid unnecessary biopsies and reduce over-diagnosis and overtreatment, was better for both RCs and slightly superior using the ERSPC-RC.

Editorial: Prostate cancer risk prediction and the persistence of uncertainty

Poyet et al. [1] have performed the largest external validation of the European Randomised Study for Screening of Prostate Cancer (ERSPC) and Prostate Cancer Prevention Trial (PCPT) v2.0 risk calculators (RCs) to date, having retrospectively identified 1996 men undergoing prostate biopsy in a Swiss tertiary care facility.

Asides from the validatory nature of this paper [1], there are several other findings though less novel, which are further important additions to the urological literature.

This study confirms the superior discriminative performance of multi-factorial RCs over PSA alone in the assessment of prostate cancer: where the area under the receiver operating characteristic curve (AUC) for the prediction of significant prostate cancer for PSA alone was 0.65, comparing less favourably than 0.73 and 0.70 for the ERSPC and PCPT v2.0 RCs, respectively.

The authors performed sensitivity analysis showing higher detection rates for prostate cancer (29.4% vs 18.1%) and significant prostate cancer (15.9% vs 5.9%) in patients receiving a 12-core biopsy than in those receiving a 6–8 core biopsy.

Supplementary analysis by the authors evaluated the performance of previous versions of the PCPT-RC, specifically v1.0 and PCPT-RC v1.0 with prostate volume. The inclusion of prostate volume demonstrated an improved predictive ability of this RC. The AUC for the prediction of significant prostate cancer using the PCPT-RC v1.0 with prostate volume was 0.74. This contrasts with the ERSPC risk tool: AUC of 0.73 (which includes a trichotomised estimation of prostate volume), and the novel PCPT-RC v2.0; AUC of 0.70 (which does not include prostate volume as a factor).

The authors conclude that the prediction of significant prostate cancer was superior using the ERSPC-RC compared with the PCPT-RC v2.0, in risk thresholds of 8–35%. Their data also shows that the PCPT-RC v2.0 offers a superior net benefit to the ERPSC-RC to a large number of men outside of this range of threshold probabilities. Their findings suggest that the older PCPT-RC v1.0 with prostate volume may offer benefits superior to both the ERSPC and PCPT v2.0 RCs.

The authors assessment of novel risk tools confirms the rationale for guidelines and consensus statements that PSA testing should not be considered on its own, but rather as part of a multivariate approach [2, 3]. This current work suggests that although calibration of risk tools is still not optimal, they offer superior discriminative ability and superior net benefit in identifying patients with significant prostate cancer. This work affirms the role for variables such as DRE, and the importance of prostate volume in addition to PSA in prostate cancer assessment.

Although further refinement of risk tools is necessary, this work encourages confidence in and should garner further traction for the routine use of such tools in the assessment and counselling of patients before prostate biopsy.

Read the full article
Dara J. Lundon*
*Conway Institute of Biomedical and Biomolecular Science, University College Dublin School of Medicine and Medical Sciences, University College Dublin, Beleld, and Department of Urology, Mater Misericordiae University Hospital, Dublin, Ireland

 

References

 

 

Article of the week: Dutch GPs influenced by ERSPC PSA study

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video of Miss van der Meer and Dr Blanker discussing their article.

If you only have time to read one article this week, it should be this one.

Impact of the European Randomized Study of Screening for Prostate Cancer (ERSPC) on prostate-specific antigen (PSA) testing by Dutch general practitioners

Saskia Van der Meer, Boudewijn J. Kollen*, Willem H. Hirdes, Martijn G. Steffens, Josette E.H.M. Hoekstra-Weebers, Rien M. Nijman and Marco H. Blanker*

Department of Urology, Isala Clinics, Zwolle, and Departments of *General Practice, Psychosocial services and Urology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

Read the full article
OBJECTIVE

• To determine the impact of the European Randomized Study of Screening for Prostate Cancer (ERSPC) publication in 2009 on prostate-specific antigen (PSA) level testing by Dutch general practitioners (GPs) in men aged ≥40 years.

MATERIALS AND METHODS

• Retrospective study with a Dutch insurance company database (containing PSA test claims) and a large district hospital-laboratory database (containing PSA-test results).

• The difference in primary PSA-testing rate as well as follow-up testing before and after the ERSPC was tested using the chi-square test with statistical significance at P < 0.05.

RESULTS

• Decline in PSA tests 4 months after ERSPC publication, especially for men aged ≥60 years.

• Primary testing as well as follow-up testing decreased, both for PSA levels of <4 ng/mL as well as for PSA levels of 4–10 ng/mL.

• Follow-up testing after a PSA level result of >10 ng/mL moderately increased (P = 0.171).

• Referral to a urologist after a PSA level result of >4 ng/mL decreased slightly after the ERSPC publication (P = 0.044).

CONCLUSIONS

• After the ERSPC publication primary PSA testing as well as follow-up testing decreased.

• Follow-up testing seemed not to be adequate after an abnormal PSA result. The reasons for this remain unclear.

 

Read Previous Articles of the Week

 

Editorial: Impact of ERSPC study on PSA testing in the Netherlands

General practitioner (GP)’s view on screening for prostate cancer in the Netherlands: the impact of a randomized trial

I am grateful to be given the opportunity to provide an editorial comment on a so-far unique publication investigating the impact of results of the European Randomized study of Screening for Prostate Cancer (ERSPC) on the attitude of Dutch GPs in requesting a serum determination of PSA in men aged >40 years. Access to data from one of the major health insurance companies and the structure and data acquisition of regional laboratories in the Netherlands provided an opportunity to carry out the project. This included the differentiation of age groups, of primary as opposed to repeat PSA testing and, in the case of the hospital database, of repeat PSA testing within 1 year, which provided the opportunity to address the primary goal of the study: the evaluation of the difference in primary PSA testing rates as well as follow-up testing before and after the 2009 publication of interim data from the ERSPC study. The fact that a Dutch translation of this publication and a recommendation by the Dutch Association of General Practitioners (Nederlands Huisartsen Genootschap, NHG) were mailed at the same time and the fact that GP guidelines had not been changed since 2005 in the Netherlands provided an important basis for the reported study.

Two different databases were used and PSA testing was evaluated 1 year before and 1 year after March 2009 (excluding the month March 2009). An overview of the data acquisition and results is given in Table 1. In brief, the data based on insurance claims show a significant decrease in PSA use before and after the 2009 publication. This decrease was less pronounced or not seen at all in men aged 70–80 or >80 years. The study selectively identified men in the ERSPC region of Rotterdam after exclusion of those assigned for re-testing in the screening arm. In line with earlier investigations, the PSA testing rate in the Rotterdam region was considerably higher then in the rest of the Netherlands. This effect was blamed on increased awareness and possibly on the motivation of men randomized into the control group of the study. The so-called ‘hospital database’ refers to a regional GP laboratory. It remains unexplained why only 2098 men of the total of 9766 men who were identified as having undergone primary PSA testing (Tables 1 and 2 in the study) were included in the analysis. These data show that there was no overall difference in testing before and after the ERSPC publication, but the proportion of re-testing decreased significantly between the two periods.

Table 1: Data acquisition and results.

Several comments can be made on this study. First, information provided on the insurance claims database allows an estimate of the proportion of men in whom PSA is evaluated (123 996/715 000 = 17.3%) and of those who undergo primary PSA testing for early diagnostic purposes (66 848/715 000 = 9.4%). The overall figure contrasts sharply with the results of a study by the Central Bureau of Statistics in the Netherlands, published in 2006. The study shows PSA use of 30–40% for the age groups 60–70 years or older.

Second, as the authors acknowledge, the differentiation between primary PSA tests for the purpose of early diagnosis and for other purposes may not be entirely reliable; however, the bias resulting from possibly incorrect assumptions is likely to be small.

Third, the sub-analysis of data coming from the Rotterdam region is likely to show the impact of greater awareness resulting from written informed consent before randomization and the effect of randomization into a control group. The data confirm an earlier evaluation of this subject (reference 7 in Van der Meer et al.) and at the same time provide a rough estimate of the level of contamination which may take place in the ERSPC study, Rotterdam region.

Fourth, it is interesting to see how age and previous PSA values influence the request for repeat PSA studies. It is counterintuitive (Table 3 in Van der Meer et al.) that even in the critical PSA range 4–10 ng/mL a significant decrease of PSA use within 1 year was seen. The multivariate analysis shows that study period before and after 2009, PSA categories and age groups are all significantly related to the decrease of PSA re-testing within 1 year.

Finally, as one of the initiators of the ERSPC study, I should like to refer to two important follow-up publications (Schröder et al.Heijnsdijk et al.) that point to the over-diagnosis and over-treatment of prostate cancer as the main reasons why the almost 30% reduction in prostate cancer mortality in screened men cannot (yet) be used for establishing population-based screening. For these reasons, the authors fully agree with the viewpoint of the Dutch GP Association and the recommendation against routine use of PSA-driven screening for prostate cancer; however, as pointed out in the last sentences of their paper instruments are now available to decrease over-diagnosis and the rate of unnecessary biopsies. In addition to that, it should be realized that men who are well informed and wish to be tested for prostate cancer cannot be refused PSA testing. To assist this process, the International Society of Urology (SIU) and the international movement ‘Movember’ have recently made available on their websites a validated decision aid for men who wish to be tested, their GPs and their treating urologists.

Fritz H. Schröder
Erasmus Medical Center, Rotterdam, The Netherlands.

Read the full article

Video: PSA testing decreased in the Netherlands after ERSPC study

Impact of the European Randomized Study of Screening for Prostate Cancer (ERSPC) on prostate-specific antigen (PSA) testing by Dutch general practitioners

Saskia Van der Meer, Boudewijn J. Kollen*, Willem H. Hirdes, Martijn G. Steffens, Josette E.H.M. Hoekstra-Weebers, Rien M. Nijman and Marco H. Blanker*

Department of Urology, Isala Clinics, Zwolle, and Departments of *General Practice, Psychosocial services and Urology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

Read the full article
OBJECTIVE

• To determine the impact of the European Randomized Study of Screening for Prostate Cancer (ERSPC) publication in 2009 on prostate-specific antigen (PSA) level testing by Dutch general practitioners (GPs) in men aged ≥40 years.

MATERIALS AND METHODS

• Retrospective study with a Dutch insurance company database (containing PSA test claims) and a large district hospital-laboratory database (containing PSA-test results).

• The difference in primary PSA-testing rate as well as follow-up testing before and after the ERSPC was tested using the chi-square test with statistical significance at P < 0.05.

RESULTS

• Decline in PSA tests 4 months after ERSPC publication, especially for men aged ≥60 years.

• Primary testing as well as follow-up testing decreased, both for PSA levels of <4 ng/mL as well as for PSA levels of 4–10 ng/mL.

• Follow-up testing after a PSA level result of >10 ng/mL moderately increased (P = 0.171).

• Referral to a urologist after a PSA level result of >4 ng/mL decreased slightly after the ERSPC publication (P = 0.044).

CONCLUSIONS

• After the ERSPC publication primary PSA testing as well as follow-up testing decreased.

• Follow-up testing seemed not to be adequate after an abnormal PSA result. The reasons for this remain unclear.

 

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