A Calculator for Prostate Cancer Risk 4 Years After an Initially Negative Screen: Findings from ERSPC Rotterdam

doi:10.1016/j.eururo.2012.07.029

European Urology

Volume 63, Issue 4, April 2013, Pages 627-633

https://doi.org/10.1016/j.eururo.2012.07.029 Get rights and content

Abstract

Background

Inconclusive test results often occur after prostate-specific antigen (PSA)–based screening for prostate cancer (PCa), leading to uncertainty on whether, how, and when to repeat testing.

Objective

To develop and validate a prediction tool for the risk of PCa 4 yr after an initially negative screen.

Design, setting, and participants

We analyzed data from 15 791 screen-negative men aged 55–70 yr at the initial screening round of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer.

Outcome measurements and statistical analysis

Follow-up and repeat screening at 4 yr showed either no PCa, low-risk PCa, or potentially high-risk PCa (defined as clinical stage >T2b and/or biopsy Gleason score ≥7 and/or PSA ≥10.0 ng/ml). A multinomial logistic regression analysis included initial screening data on age, PSA, digital rectal examination (DRE), family history, prostate volume, and having had a previous negative biopsy. The 4-yr risk predictions were validated with additional follow-up data up to 8 yr after initial screening.

Results and limitations

Positive family history and, especially, PSA level predicted PCa, whereas a previous negative biopsy or a large prostate volume reduced the likelihood of future PCa. The risk of having PCa 4 yr after an initially negative screen was 3.6% (interquartile range: 1.0–4.7%). Additional 8-yr follow-up data confirmed these predictions. Although data were based on sextant biopsies and a strict protocol-based biopsy indication, we suggest that men with a low predicted 4-yr risk (eg, ≤1.0%) could be rescreened at longer intervals or not at all, depending on competing risks, while men with an elevated 4-yr risk (eg, ≥5%) might benefit from immediate retesting. These findings need to be validated externally.

Conclusions

This 4-yr future risk calculator, based on age, PSA, DRE, family history, prostate volume, and previous biopsy status, may be a promising tool for reducing uncertainty, unnecessary testing, and overdiagnosis of PCa.

Introduction

The path from (early) diagnosis to treatment of prostate cancer (PCa) includes numerous decision points. This characteristic has led to the development of evidence-based prediction models, often presented as nomograms [1], [2] or Internet-based risk calculators [3], [4], [5]. A recent review of 36 of these types of prediction tools showed, in all studies, improvements in predictive ability compared with making the decision to biopsy based on a serum prostate-specific antigen (PSA) level alone [6].

These prediction tools, however, assess the current risk of having PCa; it is not well known how current risk relates to future risk of PCa. Men with a negative prostate biopsy may have clinical characteristics that suggest the presence of PCa. Guidance in the decision on how and when to retest (ie, PSA determination, prostate biopsy, or both) is hence urgently needed.

Baseline PSA is a powerful predictor of developing PCa [7] but in itself is insufficient to predict future risk reliably. Additional information, such as family history, prostate volume, and the outcome of any previous biopsies, needs to be considered as well [8], [9].

We aimed to develop a multivariable risk calculator to predict the 4-yr risk of having PCa after an initially negative screen. Such a calculator should support decision making in future screening or diagnostic procedures.

Section snippets

Study population

Data were derived from 21 210 men randomized to the intervention arm of the Dutch section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) (Rotterdam, 1993–1999). A total of 19 970 men (94.2%) aged 55–74 yr underwent a first-time screening by serum PSA, digital rectal examination (DRE), and transrectal ultrasonography (TRUS). If the DRE, TRUS, or both were considered suspicious, and/or the PSA was ≥4.0 ng/ml, the patient was eligible for lateralized sextant transrectal

Results

A total of 15 791 men screened at the initial screening round of ERSPC Rotterdam form the study cohort (Fig. 1). At the 4-yr repeat screening, 12 103 men were actually screened. Of these men, 2120 underwent biopsy while PSA was ≥3.0 ng/ml, and 668 men underwent biopsy while PSA was 1.1–2.9 ng/ml. At biopsy, 524 PCa cases were detected, while 40 cancers surfaced clinically during the 4-yr screening interval. Hence, a total of 564 PCa cases were detected (cancer detection rate: 564 of 15 791

Discussion

By using PSA and other relevant information available at the time of initial screening, it is possible to accurately predict future risk of having LR PCa and HR PCa. The risk calculator is based on readily available information without the necessity of further invasive procedures. The Internet-based presentation might make the calculator an easily applicable tool to support shared decision making in an individualized future screening strategy.

General practitioners and urologists are

Conclusions

The proposed 4-yr risk calculator is a promising tool in reducing uncertainty, unnecessary testing, and overdiagnosis of PCa, which are all strongly associated with screening solely based on PSA. Further validation, however, is required. In addition, physicians should always balance the calculated future risks of PCa against potential competing risks of dying from other causes.

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Cited by (35)

Predictive factors of prostate cancer diagnosis with PSA 4.0–10.0 ng/ml in a multi-ethnic Asian population, Malaysia
2020, Asian Journal of Surgery
To identify the associated factors determining prostate cancer detection using transrectal ultrasound (TRUS)-guided prostate biopsy, within a multi-ethnic Malaysian population with prostate specific antigen (PSA) between 4.0 and 10.0 ng/ml.
Study subjects included men with initial PSA between 4.0 and 10.0 ng/ml that have undergone 12-core TRUS-guided prostate biopsy between 2009 and 2016. The prostate cancer detection rate was calculated, while potential factors associated with detection were investigated via univariable and multivariable analysis.
A total of 617 men from a multi-ethnic background encompassing Chinese (63.5%), Malay (23.1%) and Indian (13.3%) were studied. The overall cancer detection rate was 14.3% (88/617), which included cancers detected at biopsy 1 (first biopsy), biopsy 2 (second biopsy with previous negative biopsy) and biopsy ≥ 3 (third or more biopsies with prior negative biopsies). Indian men displayed higher detection rate (23.2%) and increased risk of prostate cancer development (OR 1.85, 95% CI 1.03–3.32, p < 0.05), compared to their Malay (9.8%) and Chinese (14.0%) counterparts. Multivariable analysis revealed that ethnicity and PSA density (PSAD) are independent factors associated with overall prostate cancer detection rate. A unit increase of PSAD reflected an increase in PSA after controlling for prostate volume.
Prostate cancer detection in Malaysia is comparatively lower. Our study suggests that ethnicity and PSA density should be considered when recommending first or repeat TRUS-guided prostate biopsy for prostate cancer detection in a multi-ethnic Malaysian population.
A prospective study investigating the impact of multiparametric MRI in biopsy-naïve patients with clinically suspected prostate cancer: The PROKOMB study
2017, Contemporary Clinical Trials
Citation Excerpt :
Clinical data including levels of serum PSA and results of DRE and TRUS are documented at the baseline visit. The Rotterdam risk calculator at the time of the baseline visit is calculated by the study coordination center [27]. All patients undergo 3 T mpMRI of the prostate exclusively at two dedicated imaging centers at the Department of Radiology at Charité - Universitätsmedizin Berlin using three identical MR scanners (Magnetom Skyra, Siemens Healthcare, Erlangen, Germany) as well as identical imaging protocols.
In patients with suspected prostate cancer (PCa) according to current guidelines systematic transrectal ultrasound (TRUS)-guided biopsy of the prostate is performed to verify or rule out PCa. However, TRUS-guided biopsy can result in underdetection of clinically significant cancers as well as diagnosis of clinically insignificant cancers. Multiparametric MRI (mpMRI) might improve the diagnostic pathway and help to avoid unnecessary biopsies.
The PROKOMB (Prostata – Kooperatives MRT-Projekt Berlin) study is a prospective two-arm multicentre study designed to evaluate the potential role of mpMRI as a triage test before biopsy. Up to 600 biopsy-naïve men with suspicion for PCa undergo mpMRI at two dedicated imaging centers. Only patients with equivocal or suspicious lesions on mpMRI undergo prostate biopsy including systematic as well as MRI-guided targeted biopsies at several different community-based urologists or hospitals. The PROKOMB study is designed to evaluate how many biopsies can be avoided, how many clinically insignificant cancers are diagnosed on prostate biopsy in patients with positive findings on mpMRI, and how many clinically significant cancers are missed using this alternative diagnostic pathway. For the purpose of this study clinically significant PCa is defined as Gleason ≥ 3 + 4 cancer. In addition, the detection rates of different techniques for MRI-guided biopsy are evaluated as well as psychological distress before mpMRI and after the diagnosis of PCa.
The PROKOMB study might help in defining the role of mpMRI in biopsy-naïve patients with suspected PCa in an ambulatory care setting.
No Detrimental Effect of a Positive Family History on Long-Term Outcomes Following Radical Prostatectomy
2016, Journal of Urology
Overall 1 in 5 patients with prostate cancer has a positive family history. In this report we evaluated the association between family history and long-term outcomes following radical prostatectomy.
Patients treated with radical prostatectomy were identified from a German registry, and separated into positive first-degree family history vs negative family history (strictly negative, requiring at least 1 male first-degree relative older than 60 years and no prostate cancer in the family). Kaplan-Meier curves and Cox proportional hazards models were used for association analyses with biochemical recurrence-free and prostate cancer specific survival.
Median followup for 7,690 men included in the study was 8.4 years. Of the 754 younger patients less than 55 years old 50.9% (384) had a family history compared to 40.4% of the older patients (2,803; p <0.001). The 10-year biochemical recurrence-free (62.5%) and prostate cancer specific survival (96.1%) rates did not differ between patients with vs without a family history, nor between the younger vs older patient groups (all p >0.05). Prostate specific antigen, pathological stage, node stage and Gleason score were the only significant predictors for biochemical recurrence-free survival, while pathological stage, node stage (all p <0.005) and Gleason score (Gleason 7 vs 6 or less—HR 1.711, 95% CI 1.056–2.774, p = 0.03; Gleason 8 or greater vs 6 or less—HR 4.516, 95% CI 2.776–7.347, p <0.0001) were the only predictors for prostate cancer specific survival.
A family history of prostate cancer has no bearing on long-term outcomes after radical prostatectomy.
Decision Support for Low-Risk Prostate Cancer
2016, Prostate Cancer: Science and Clinical Practice: Second Edition
Since the introduction of prostate-specific antigen for the early detection of prostate cancer, overdiagnosis and subsequent overtreatment have become more and more apparent. Conservative treatment options, specifically active surveillance, are therefore becoming increasingly used in an attempt to reduce the morbidity of radical treatment. Several clinical prediction models were developed to assess an individual’s risk of having indolent prostate cancer. Those with high probabilities of indolent cancer are best suited for conservative management. Prediction models readily provide detailed risk estimates when presented as nomograms, which is preferable over simpler presentations as rules. Incorporation of prediction models into decision aids is a good way of providing the best of care for men facing a treatment decision of low-risk prostate cancer with improved patient knowledge and more conscious treatment choices. In this chapter, different currently available nomograms are discussed, with considerations to select the most appropriate nomogram for an individual patient.
What risk of prostate cancer led urologist to recommend prostate biopsies?
2015, Progres en Urologie
Citation Excerpt :
Recently, the integration of biomarkers (PHI index, PCA3 score) in these programs improved their accuracy [27]. Roobol et al. reported that the urologists may be able to select the individual screening schedule based on the risk threshold calculated in the last visit [28]. If the prostate cancer overdiagnosis and the increased number of prostate biopsies in France are debatable issues, the patients biopsied in this study had a higher risk of prostate cancer, calculated by the nomogram, than other studies.
The aim of this study was to estimate the risk of prostate cancer that led urologists to perform prostate biopsies.
Eight hundred and eight patients had prostate biopsies in 5 tertiary centres in 2010. Following data were collected: age, PSA, DRE, prostate volume, negative prior prostate biopsy and estimated life expectancy (> or < 10 years). The risk of prostate cancer was calculated by validated nomogram of PCPT-CRC and SWOP-PRI and correlated with pathological biopsy results.
In final analysis, 625 patients were included, 568 (90.9%) had a life expectancy greater than 10 years. Prostate cancer was found in 291 (46.6%) cases. These patients were older (66.7 ± 6.8 vs 64.3 ± 5.6 years, P < 0.001), had higher PSA values (10 ± 7.9 vs 7.7 ± 4.3 ng/mL, P < 0.0001) and the prostate volume decreased (43.8 ± 19.8 vs 51.3 ± 20.7 mL, P < 0.0001) compared with healthy subjects. Digital Rectal Examination was more frequently suspicious in the group of patients with prostate cancer (43.6% vs 18.9%, P < 0.0001). Risk of prostate cancer estimated was 50.6 ± 14% for PCPT-CRC without ATCD, 56.2 ± 12.8% with PCPT-CRC ATCD and 31.2 ± 17.3% for SWOP-PRI. The likelihood of high-risk prostate cancer was 22.4 ± 16.9% with the PCPT-CRC, and 14.8 ± 18.2% with SWOP-PRI.
This study showed that urologists performed prostate biopsies when the risk of cancer was high.
5.
Déterminer quel niveau de risque de cancer conduit les urologues français à réaliser des biopsies de la prostate.
Il s’agissait d’une étude portant sur 808 patients ayant eu des biopsies de la prostate dans 5 centres universitaires français en 2010. Les données suivantes étaient colligées : l’âge, le PSA, le toucher rectal, le volume prostatique et le nombre de série de biopsies préalables. L’espérance de vie était estimée (supérieure ou inférieure à 10 ans) par l’urologue. Les résultats anatomopathologiques des biopsies étaient renseignés. À partir de ces données, le risque de cancer était calculé par les nomogrammes validés du PCPT-CRC et du SWOP-PRI.
Six cent vingt-cinq patients étaient inclus pour l’analyse finale, 568 (90,9 %) avaient une espérance de vie supérieure à 10 ans. Un cancer de la prostate était retrouvé sur les biopsies systématisées chez 291 patients (46,6 %). Ces patients étaient plus âgés (66,7 ± 6,8 vs 64,3 ± 5,6 ans, p < 0,001), avaient un PSA plus élevé (10 ± 7,9 vs 7,7 ± 4,3 ng/mL, p < 0,0001) et un volume prostatique diminué (43,8 ± 19,8 vs 51,3 ± 20,7 mL, p < 0,0001) par comparaison aux sujets sains. Le toucher rectal était plus fréquemment anormal dans la population malade (43,6 % vs 18,9 %, p < 0,0001). Les niveaux de risque incitant les urologues à biopsier étaient en moyenne pour les nomogrammes PCPT-CRC sans ATCD de 50,6 ± 14 %, PCPT-CRC avec ATCD de 56,2 ± 12,8 % et pour le SWOP-PRI de 31,2 ± 17,3 %. La probabilité que les biopsies détectent un cancer de haut grade était avec le PCPT-CRC de 22,4 ± 16,9 % et de 14,8 ± 18,2 % avec le SWOP-PRI. Les niveaux de risque augmentaient avec l’âge, étaient différents entre les patients déjà biopsiés et indemnes de biopsies pour les deux calculateurs de risque.
Si le surdiagnostic est une préoccupation actuelle des hautes autorités de santé, ce travail montre que les urologues tolèrent un niveau de risque de cancer prostatique élevé avant de faire des biopsies.
5.
Repeat Prostate Biopsy: Rationale, Indications, and Strategies
2015, European Urology Focus
Citation Excerpt :
In a PSA screening scenario, the risk of having PCa 4 yr after an initially negative screen is <4%. In this case, the indication for RB should be evaluated according to patient age, PSA level, digital rectal examination (DRE), family history, and prostate volume [6]. Finally, in the most recent guidelines, the use of additional biomarkers has been suggested to improve specificity in the RB setting (Table 1).
The inaccuracy of prostate biopsy in detecting and characterising prostate cancer (PCa) has led to a widespread use of repeat biopsy (RB).
To summarise the most recent data regarding indication, techniques, and clinical implications of RB.
A search of Medline, PubMed, and Scopus identified articles published in the last 7 yr (2008–2014) addressing the role of RB in the PCa setting. Abstracts deemed relevant to the defined review question were screened, and the data were extracted, analysed, and summarised.
RB can be considered either in patients with persistent PCa suspicion after a first negative systematic biopsy or during active surveillance (AS), either to confirm patient enrolment or to monitor the natural progression of the disease. Indication and biopsy techniques differ according to each PCa scenario. Magnetic resonance imaging (MRI)-guided RB has been gaining popularity because of its accuracy in detecting and characterising PCa. Indications for multiple RBs (eg, AS setting) should be carefully evaluated because of the cumulative risk of complications, especially infection. In the next few years, clinical and genetic markers are expected to further improve the ability to determine the need for RB.
RB indications and techniques in persistent PCa suspicion and AS should take into account the evolving field of imaging, management options, and the risk of possible complications. In an RB setting, the introduction in daily clinical practice of MRI-guided targeted biopsy has improved the accuracy in detecting PCa without significantly increasing the risk of finding indolent, low-risk PCa. Referral to specialised care centres should be considered in patients with persistent PCa suspicion to provide the most rationalised management in terms of indication, biopsy technique, complications, pathologic assessment, and, finally, clinical implications of the findings.
A man may require a second prostatic biopsy for a number of reasons. In the current report, we describe why, when, and how a patient should undergo rebiopsy of the prostate.

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^†: These authors contributed equally to this article.

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Platinum Priority – Prostate CancerEditorial by Noel W. Clarke on pp. 634–635 of this issueA Calculator for Prostate Cancer Risk 4 Years After an Initially Negative Screen: Findings from ERSPC Rotterdam

Abstract

Background

Objective

Design, setting, and participants

Outcome measurements and statistical analysis

Results and limitations

Conclusions

Introduction

Section snippets

Study population

Results

Discussion

Conclusions

Eur Urol

J Urol

Eur Urol

Eur Urol

Eur Urol

J Urol

Urology

Eur Urol

J Urol

Eur J Cancer

Lancet Oncol

J Clin Epidemiol

Eur Urol

J Urol

Role of nomograms for prostate cancer in 2007

World J Urol

Platinum Priority – Prostate Cancer
Editorial by Noel W. Clarke on pp. 634–635 of this issue
A Calculator for Prostate Cancer Risk 4 Years After an Initially Negative Screen: Findings from ERSPC Rotterdam