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Keywords:

  • serendipity;
  • prostate cancer;
  • detection;
  • screening;
  • PSA

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors

Objective To assess the magnitude of prostate cancer detection by serendipity (the coincidental detection of prostate cancer during the evaluation of an abnormal screening test result) when a digital rectal examination (DRE) and transrectal ultrasonography (TRUS) are used as initial screening tests for prostate cancer in men with low levels of prostate-specific antigen (PSA; 0.0–3.9 ng/mL).

Patients and methods In all, 117 participants of a population-based screening study were diagnosed with prostate cancer after a standard evaluation of an abnormal screening test result; 49 underwent radical prostatectomy. Serendipity was defined as either: (i) the presence of prostate cancer opposite to the side that raised suspicion for cancer on DRE and/or TRUS; (ii) a negative lesion-directed biopsy while cancer was present in one or more of the cores of the sextant biopsy; (iii) a tumour volume of < 0.5 mL on radical prostatectomy.

Results Depending on the definition, 27–63% of prostate cancers detected at low PSA values were detected coincidentally and not as a result of a true-positive test result. The proportion of cancers detected by serendipity was inversely correlated with serum PSA level.

Conclusion A relatively high proportion of prostate cancers diagnosed in men with low PSA levels, and in which a biopsy was prompted by a suspicious DRE and/or TRUS, are considered to be detected by chance only. As these cancers are mostly small (< 0.5 mL), with potentially low biological aggressiveness, relying on serendipity seems disadvantageous in prostate-cancer screening. The level of serendipity in prostate cancer detection, the poor performance of the screening test, and high inter-observer variability, casts further doubt on the utility of DRE (and TRUS) as initial screening tests for prostate cancer in population-based screening.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors

Population-based screening for prostate cancer by a DRE and PSA testing remains a controversial issue. To date screening for prostate cancer has not yet been confirmed to reduce prostate cancer mortality in randomized controlled trials (RCTs), and the validity and usefulness of the screening tools are not completely understood. Despite these concerns, the American Cancer Society and the AUA believe that, as preventive healthcare policy, annual PSA testing and a DRE should be offered to all men geqslant R: gt-or-equal, slanted50 years old, and from 45 years old in men in high-risk groups [1,2]. However, the USA Preventive Services Task Force, the Canadian Urological Association and most health authorities within the European Union discourage prostate-cancer screening, while the recommendations of the American College of Physicians and the American Academy of Family Physicians are currently under review [3–5].

In men with a PSA level of 0.0–3.9 ng/mL the use of a DRE as a screening test for prostate cancer has recently become the topic of serious debate. Adversaries of DRE as a screening test for prostate cancer indicate the poor performance of this test at low PSA values and its high inter-observer variability [6–9]. Advocates merely refer to the independent predictive value of a DRE for prostate cancer, complementary to PSA testing, and indicate that some potentially aggressive cancers may remain undetected if a DRE was omitted as a screening test [1,10,11]. In North America, the current dispute has even reached a judicial level (Schröder FH, personal communication).

A screening test may be positive because the disease that is the primary objective of the screening test is present (true positive), or it may be positive because there are morbidities not related to the disease (false positive). The target disease may also be detected coincidentally during the evaluation of a false-positive screening test result. The detection of the disease cannot then be attributed to the screening test itself. This mechanism of the coincidental detection of disease has earlier been defined as ‘serendipity’[12]. In early detection programmes for prostate cancer, systematic sextant biopsy and additional lesion-directed biopsy from suspicious areas of the prostate gland is prompted in men with abnormal screening test results, and thus prostate cancer detection by serendipity is likely. As small prostate cancers are unlikely to be palpable on DRE and/or visible on TRUS, indicating that the abnormal screening test alone might not have been responsible for detecting the disease.

In the present study the magnitude of prostate cancer detection by serendipity (chance) was determined when a DRE alone and combined with TRUS was used as an initial screening test for prostate cancer in men with low PSA values (0.0–3.9 ng/mL). The data were obtained from the screening arm of a large population-based RCT, the European Randomized Study of Screening for Prostate Cancer (ERSPC). These results provide an additional insight into the performance of DRE and TRUS as screening tests for prostate cancer in this highly contentious PSA range.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors

The present data were derived from the prevalence screen of a multi-institutional population-based RCT (ERSPC, Rotterdam section) investigating the effect of systematic screening for prostate cancer on cancer-specific mortality and quality of life. The conditions and algorithm of the screening regimen of the ERSPC are described in detail elsewhere [13–16]. Between June 1994 and February 1997, 10 226 men (aged 55–74 years) were randomized to the screening arm of the ERSPC. In all screened participants, PSA testing, a DRE and TRUS were applied as initial screening tests for prostate cancer. Blood was sampled before the DRE, so that the DRE and TRUS were undertaken with no knowledge of the PSA value. Participants were informed about the PSA value and the findings on DRE and TRUS by letter, and were notified about the procedure to be followed. In those in the low PSA range (0.0–3.9 ng/mL), men with a suspicious DRE (nodularity, asymmetry, induration) or TRUS (hypo-echogenicity) finding were invited to undergo prostate needle biopsy at a second visit. Systematic transrectal sextant biopsies were taken using a spring-loaded biopsy gun and an 18 G biopsy needle, as described elsewhere [16]. Additional biopsies were taken from any suspicious areas within the prostate gland. TRUS-guidance was provided by a 7-MHz end-fire ultrasound probe. The cancer detection rates, positive predictive values (PPVs) of the screening test and the number of biopsies needed to detect one cancer were outlined by Schröder et al.[15].

All separate biopsy cores were labelled and processed for routine histopathological examination, and patients with prostate cancer were offered treatment, guided by their urologist. Radical prostatectomy specimens were routinely fixed and processed according to well-established protocols [17,18], and morphometric analysis undertaken to determine the tumour volume, as described in detail earlier [19].

Detecting prostate cancer serendipitously might be defined in three ways. (i) As the presence of prostate cancer opposite to the side that raised suspicion for cancer on DRE or TRUS and prompted the biopsy. To assess how often prostate cancer might be detected serendipitously, the side of the abnormal screening test (left/right/bilateral) was compared with the side of the tumour on needle biopsy (left/right/bilateral). Inconsistencies were considered to define serendipitous detection. The contribution of DRE and TRUS to serendipity alone was determined by excluding cases in which the other screening test was also abnormal. (ii) A more precise indication of the magnitude of serendipity might be given by defining serendipitously detected cancers to be those in which the cancer was diagnosed in one of the cores of the biopsy sextant, while the biopsy that was specifically directed at the suspicious area of the prostate gland (and that prompted the biopsy) remained free of disease. (iii) Serendipitously detected cancers could be defined as those in which the tumour volume, as determined in the radical prostatectomy specimen, was not likely to cause the screening tests (DRE or TRUS) to be suspicious for cancer. A perfect sphere of 0.5 mL has a diameter of almost 1 cm (4/3πr3 = 0.5 mL) and we assumed that this is the borderline of palpability on a DRE and of visualization on TRUS. Consequently, prostate cancers with a tumour volume of < 0.5 mL were also assumed to be detected serendipitously. The dependency of the percentage of serendipitous findings on the 0.5 mL volume threshold was assessed by repeating the calculations for threshold volumes of 0.4, 0.25 and 0.1 mL (sensitivity analysis).

The Pearson χ2-test was used to assess the trend between the serum PSA level and the frequency of serendipitously detected cancers. The assumption that no difference existed for the variable evaluated was rejected if P <0.05.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors

At low PSA levels, 117 men were diagnosed with prostate cancer after evaluating a suspicious screening test, 40 (34%) after an abnormal DRE alone and 39 (33%) after an abnormal TRUS alone. Using the outcome of both screening tests (DRE and TRUS), 31 of 117 (27%) cancers were detected on the side of the prostate gland other than the palpable or visibly suspicious area that prompted the biopsy (Table 1). On the basis of a suspicious DRE alone, serendipity accounted for 15 of 40 (37%) cases, and 13 of 39 (33%) cancers diagnosed after a suspicious TRUS alone. There was no association with the number of these serendipitously detected cancers and serum PSA level.

Table 1.  The frequency of prostate cancer detection by serendipity (the presence of prostate cancer opposite to the side of the prostate that raised suspicion for prostate cancer and prompted the biopsy) in patients diagnosed with prostate cancer in low PSA ranges, and in those who had additional lesion-directed biopsies (where serendipity was defined as the presence of prostate cancer in one of the cores of the sextant biopsy, while the biopsy that was specifically directed at the suspicious area of the prostate gland remained negative for cancer), and in those undergoing radical prostatectomy (where serendipity was defined as cancers with a tumour volume of < 0.5 mL)
Screening tool/testNPSA, ng/mLTotal
0.0–0.91.0–1.92.0–2.93.0–3.9
  1. χ2-test for trend; *P=0.72, P=0.79, P=0.34, P=0.08 and §P=0.03.

DRE and TRUS*117   
 Serendipity, n (% of subtotal) 1 (25)14 (33)6 (22)10 (23)31 (27)
 Subtotal, n (% of N) 4 (3)43 (37)27 (23)43 (37)117
DRE alone 40   
 Serendipity, n (% of subtotal) 1 (50)6 (46)3 (27)5 (36)15 (37)
 Subtotal, n (% of N) 2 (5)13 (34)11 (28)14 (35)40
TRUS alone 39   
 Serendipity, n (% of subtotal) 07 (47)3 (21)3 (30)13 (33)
 Subtotal, n (% of N) 015 (39)14 (36)10 (26)39
Additional lesion-directed biopsy 75   
 Serendipity, n (% of subtotal) 2 (100)10 (36)6 (40)6 (20)24 (32)
 Subtotal, n (% of N) 2 (3)28 (37)15 (20)30 (40)75
Radical prostatectomy§ 49   
 Serendipity, n (% of subtotal) 2 (100)16 (84)8 (53)5 (38)31 (63)
 Subtotal, n (% of N) 2 (4)19 (39)15 (31)13 (27)49

Overall, 75 of 117 (64%) men who were later diagnosed with prostate cancer underwent additional lesion-directed biopsy. In men in whom no additional lesion-directed biopsy was taken the original suspicious lesion that prompted the biopsy could not be retrieved at second visit, or was found to be at the opposite side from that at the first visit. In these men it was decided to take a sextant biopsy only. In 24 (32%) men who underwent additional lesion-directed biopsy, prostate cancer was present in one or more of the cores of the biopsy sextant only (Table 1). The number of prostate cancers detected coincidentally showed an inverse trend with rising PSA values (P = 0.08), and the proportion of serendipitously detected cancers declined from 100% in the PSA range 0.0–0.9 ng/mL to 20% in the range 3.0–3.9 ng/mL.

The absolute number and the relative proportion of 49 men who were surgically treated and who had a tumour volume of <0.5 mL is also given in Table 1. The frequency of these serendipitously detected cancers was inversely correlated with serum PSA level (P = 0.03), and the proportion of cancers found coincidentally steadily declined from 100% at a PSA of 0.0–0.9 ng/mL to 38% at 3.0–3.9 ng/mL (Table 1). Serendipity still accounted for 55%, 37% and 24% of detected cancers if a tumour volume of 0.4, 0.25 or 0.1 mL, respectively, was used as a threshold.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors

At present both the serum PSA test and DRE are used for the early detection of prostate cancer. There is wide acknowledgement that using the serological PSA test has substantially improved the ability to detect prostate cancer. In the early 1990s its introduction led to a major increase in the incidence of prostate cancer, and particularly to an increase in organ-confined and therefore potentially curable disease [20,21]. However, a beneficial effect of screening has not yet been established, and thus the major health authorities in several European countries discourage opportunistic prostate cancer screening. In their considerations, a reference was made to the early signs of success in the lung-cancer screening trials performed in the 1970s [22]. Despite a substantial stage shift caused by screening, RCTs show no difference in lung cancer mortality between those screened and those who were not. Also for prostate cancer, only well-performed RCTs will eventually provide a final answer to the question of whether screening is more beneficial than harmful [23–24]. Until the outcome of these RCTs is reported, efforts should be made to optimize the applied screening approach. This implies an extensive study of the validity of the screening tests, their effects on the quality of life of those screened, and an evaluation of healthcare-related costs.

At low PSA ranges (0.0–3.9 ng/mL) the DRE is the mainstay of early detection; this screening test has been considered complementary to the PSA test, while its performance is PSA-dependent and its application requires skilled examiners [2]. Recently, the use of the DRE as a screening test for prostate cancer has been criticised for its subjectivity, with high inter-observer variability [9], and its poor performance relative to the serum PSA test [21]. There is even a suggestion that the DRE as an initial screening test for prostate cancer might be discarded in those with low PSA values [8,15]. In this PSA range the reported cancer detection rates are low and the PPV of the screening test ‘less than desirable’[6,7]. In the ERSPC, the PPV of a DRE was 4–33% in men with PSA levels within the ‘normal’ range (0.0–3.9 ng/mL), with a mean of 8.8% in men with a PSA level of < 3.0 ng/mL [6]. The PPV of TRUS was also low, i.e. 0% at a PSA of 0.0–0.9 ng/mL and 11% at a PSA of 1.0–3.9 ng/mL. The relatively poor performance of the DRE has also been reported elsewhere [6,25–28]. A recent report from our department clarified that the yield of rectal examination (both DRE and TRUS) for detecting prostate cancer was extremely low in those with low PSA values. From a population-based study, we calculated that at PSA levels of < 3.0 ng/mL, 96 DREs were required to find one case of prostate cancer of any size, grade or stage, and 289 DREs were needed to find one cancer with assumable clinically significant tumour features [8]. These values were substantially higher at even lower PSA ranges. The appropriate ethical reaction to these values is a question that must be considered by primary healthcare providers and by those who will eventually finance the nationwide screening programme.

The cited studies all had in common that positive screening test results were considered true positives, i.e. that the observed abnormalities on DRE or TRUS were caused by the cancer in question. However, the true informative value of a screening test may be overestimated if cancers are subsequently detected after evaluating a false-positive screening test result. In prostate cancer screening, these false-positives are mainly caused by BPH or prostatitis. The method of tissue sampling in prostate cancer screening (i.e. sextant biopsy and lesion-directed biopsies from suspicious areas) and the recognition of favourable prognostic indicators (e.g. low tumour volumes) enable the serendipitous coincidental detection of disease [8]. The results of the present population-based screening study indicate that, depending on the definition of serendipity, 27–63% of men with prostate cancer who were detected from a PSA range of 0.0–3.9 ng/mL, and in whom a biopsy was prompted by a suspicious DRE or TRUS, were detected coincidentally. The frequency of serendipitously detected cancers was inversely correlated with the serum PSA level and serendipity accounted for proportionally more cases if the DRE was used independently of TRUS (Table 1). Considering that most serendipitously detected cancers in the PSA range 0.0–3.9 ng/mL had tumour volumes of < 0.5 mL (Table 1) the acceptance of serendipity might not be advantageous in early-detection programmes for prostate cancer. Small prostate tumours are not considered a primary target in RCTs, i.e. the main target being those that are responsible for future prostate cancer mortality, and it may be assumed that patients who are eventually diagnosed with these seemingly ‘biologically insignificant’ cancers might have been suitable candidates for conservative therapy and close surveillance if untreated [29–31]. The assumption that these small cancers are biologically insignificant may be supported by the observation that most prostate cancers with tumour volumes of < 0.5 mL are organ-confined and lack poorly differentiated components [29–31]. With a rising tumour volume and a PSA value increasing correspondingly, it is likely that these cancers will be detected at a curable stage in successive screening rounds. Even if these men with small prostate cancers are likely to present clinically in the future, and their tumours are destined to cause future morbidity and/or mortality, relying on chance to detect them may not be a desirable screening objective.

Estimating prostate cancer detection by serendipity was based on arbitrary assumptions in this study and the actual magnitude of this coincidental detection of disease might differ widely from the values given here. As more than half of the biopsy cores (the lesion-directed biopsy and three unilateral biopsies within the sextant) were directed to the side that was suspicious for cancer, the magnitude of serendipity may be underestimated. Bilateral suspicious screening tests may also cause serendipity to be under-reported, as these cases can only be classified as true-positives using this definition of serendipity. Conversely, it is likely that an investigator's finding of a particular suspicious side on DRE or TRUS may sometimes be erroneously reported (i.e. left vs right, or vice versa) because patients are in the left lateral decubitus position. Consequently, any inconsistencies in DRE and/or TRUS findings between first (screening tests) and second (biopsy) screening visits were not followed by additional lesion-directed biopsies. This low compliance rate to additional biopsy may thus have overestimated the magnitude of serendipity. Also, a palpable or hypoechoic lesion may still contain cancer even though the lesion-directed biopsy was negative for cancer through sampling error. In these cases in which cancer was coincidentally found in one of the cores of the biopsy sextant, claiming serendipity seems premature. The threshold tumour volume of 0.5 mL to define serendipity was arbitrarily chosen; perfect spheres with these volumes might still be palpable on DRE or visible on TRUS. However, prostate cancers are often ovoid and multifocal, indicating that the likelihood of DRE or TRUS being suspicious for cancer is reduced. Moreover, sensitivity analysis showed that serendipity still accounted for 55%, 37% and 24% of the detected prostate cancers when threshold volumes of 0.4, 0.25 and 0.1 mL, respectively, were used.

From the relatively high contribution of serendipity (chance) in prostate cancer detection, and from earlier studies reporting the poor performance of DRE and TRUS as screening tests for prostate cancer (and their high inter-observer variability) we cast further doubt on the utility of DRE and TRUS as screening tests for prostate cancer in low PSA ranges. To avoid unnecessary testing, to increase compliance rates with population-based screening, and to encourage cost-effective screening programmes, the complete omission of the DRE and TRUS as initial screening tests for prostate cancer might be considered within these low PSA ranges.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors

The ERSPC is supported by ‘Europe Against Cancer’, a programme of the European Union, and Hybritech Incorporated. The Rotterdam section is financed by the Dutch Cancer Society and the Dutch Prevention Fund.

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Authors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors

A.N. Vis, MD, Resident in Urology.

R. Kranse, BSc, Statistician.

M. Roobol, BSc, Datamanager ERSPC.

Th.H. van der Kwast, MD, PhD, Professor of Pathology.

F.H. Schröder, MD, PhD, Professor of Urology.

Abbreviations
RCT

randomized controlled trial

ERSPC

European Randomized Study of Screening for Prostate Cancer

PPV

positive predictive value.

A.N. Vis, Department of Pathology and Urology, Josephine Nefkens Institute, Erasmus University, PO Box 1738, 3000 DR Rotterdam, The Netherlands. e-mail: vis@path.azr.nl