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European Urology
Volume 57, issue 2, pages 179-362, February 2010Prostate Cancer
Eleven-Year Outcome of Patients with Prostate Cancers Diagnosed During Screening After Initial Negative Sextant Biopsies
Fritz H. Schröder 
, Roderick C.N. van den Bergh, Tineke Wolters, Pim J. van Leeuwen, Chris H. Bangma, Theo H. van der Kwast, Monique J. Roobol.
Accepted 27 October 2009, Published online 6 November 2009, pages 256 - 266
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Abstract
Background
The appropriate way of biopsying a prostate remains controversial. Is sextant biopsy still adequate with repeat screening?
Objective
Within the European Randomized Study of Screening for Prostate Cancer (ERSPC), lateralized sextant biopsies were applied. In this analysis we use distant end points to study the fate of prostate cancers (PCa) potentially missed by initial biopsies.
Design, setting, and participants
This retrospective study included 19 970 men ages 55–74 identified from the Rotterdam population registry and screened repeatedly for PCa between 1993 and 2005. PCa detected later in men with initially negative biopsies were considered as missed. Rescreening every 4 yr and a complete follow-up of 11 yr allowed an inventory of progressive and deadly disease in these men.
Intervention
Sextant biopsies initially, later lateralized, in screen-positive men.
Measurements
The fate of PCa potentially missed by initial sextant biopsies in terms of progression-free and PCa-specific survival were the main outcome measures. Kaplan-Meier analysis was used to evaluate differences between subgroups.
Results and limitations
In 3056 men with negative biopsies at the first screen, 287 PCa were subsequently detected. Of these 287 cases, 26 developed progressive disease and 7 died of PCa. Poor outcomes were encountered mainly in 20 interval cases. The seven PCa deaths in men with initially negative biopsies amounted to only 0.03% compared to the 0.35% PCa death rate in the whole population of 19 970 men. Limitations include the retrospective character of this analysis.
Conclusions
The number of potentially missed cancers with a poor outcome in terms of progression-free survival and deaths from PCa is very low. Despite some limitations, our data show that lateralized sextant biopsy is not obsolete if repeated screening is applied.
Keywords: Prostate cancer, PSA, Sextant prostate biopsy, Screening, Progression, Prostate cancer mortality.
Article Outline
1. Introduction
Screening for prostate cancer (PCa) is prevalent around the world. Recently the European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown significant reductions in PCa mortality in an intention-to-screen analysis (20%) [1] and in an analysis adjusted for noncompliance and contamination (30%) [2]. Present uncertainties include the best way to biopsy the prostate. Within ERSPC Rotterdam up to June 1996, the classical sextant biopsy technique was applied [3]. After a report by Eskew et al in 1996 [4] on the effects of taking more biopsies including the lateral peripheral zones, the biopsy procedure was changed to taking six biopsies from the lateral peripheral zone. In the meantime, an extensive literature has developed that shows that sextant biopsies as well as lateralized sextant biopsies underdiagnose PCa in comparison to more extensive biopsy procedures.
Seven recent publications [4], [5], [6], [7], [8], [9], and [10] allow a comparison between the percentage of PCa detected in clinical settings by extended biopsy schemes and classical sextant and lateralized sextant biopsies (Table 1). Overall, these studies report on >4000 biopsied men in whom 1781 cancers (41%) were found. Classical sextant biopsies and lateralized sextant biopsies would have missed 23% and 19% of detectable cancers, respectively.
Table 1 Prostate cancer (PCa) detected or missed with extended versus lateralized sextant versus traditional sextant scheme
| Reference | Extended scheme | Lateralized sextant scheme | Traditional sextant scheme | Traditional sextant plus additional lateral cores | ||||
|---|---|---|---|---|---|---|---|---|
| Extended biopsy scheme | Extended cores, n | Lateralized sextant biopsy | Missed PCa | Traditional sextant biopsy | Missed PCa | Sextant plus four lateral cores | Missed PCa | |
| PC/n (%) | – | PC/total PC (%) | n (%) | PC/total PC (%) | n (%) | – | – | |
| De la Taille et al [5] | 806/2133 (37.8)* | 21 | 637/806 (79.0)* | 169 (21.0) | 598/806 (74.2)* | 208 (25.6) | 387/415 (93) | 28 (7) |
| Epstein et al [6] | 123*/– (–) | 12 | 108/123 (88) | 15 (12) | 92/123 (75) | 31 (25) | – | – |
| Eskew et al [4] | 48/119 (40) | 13 | – | – | 31/48 (65) | 17 (35) | 46/48 (95.8) | 2 (4.2) |
| Neill et al [7] | 494/1010 (49) | 10 | 387/494 (78)** | 107 (22) | 411/494 (83) | 83 (17) | – | – |
| Presti et al [8] | 202/483 (41.8) | 10 | 180/202 (89.1) | 22 (10.9) | 161/202(79.7) | 41 (20.3) | 194/202 (96.0) | 8 (4.0) |
| Gore et al [9] | 68/178 (38.2) | 12 | 58/68 (85.3) | 10 (14.7) | 47/68 (69.1) | 21 (30.9) | 60/68 (88.2) | 8 (11.8) |
| Paul et al [10] | 40/100 (40) | 10 | 34/40 (85.0) | 6 (15) | – | – | – | – |
| Total | 1781 | – | 1404/1733 (81.0) | 329 (19.0) | 1340/1741 (77.0) | 401 (23.0) | 687/733 (93.7) | 46 (6.3) |
*
**
Fourteen representative publications applied second biopsies after a negative initial biopsy. After various periods of time, 2121 cancers were detected in 9166 men (23.1%) [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], and [24]. Clearly, the proportion of PCa found with extended biopsy schemes and with repeat second biopsies after initial sextant biopsies are rather similar, indicating that about 23% of biopsy-detectable PCa are missed at initial sextant biopsies taken in the classic locations (Table 2).
Table 2 Prostate cancer (PCa) detected at second biopsy after initial negative sextant biopsies (different repeat biopsy schemes and biopsy indications were used)
| Reference | Population | Repeat biopsy PCa/n (%) |
|---|---|---|
| Keetch et al [11] | Screening | 82/427 (19) |
| Roehrborn et al [12] | Clinic | 28/123 (23) |
| Fleshner et al [13] | Clinic | 39/130 (30) |
| Rietbergen et al [14] | Screening | 49/442 (11) |
| Letran et al [15] | Clinic | 15/51 (29) |
| Djavan et al [16] | Clinic/screening | 83/820 (10) |
| O’Dowd et al [17] | Clinic | 1637/6380 (26) |
| Lujan et al [18] | Clinic | 27/172 (16) |
| Stewart et al [19] | Clinic (saturation after sextant) | 77/224 (34) |
| Lane et al [20] | Clinic (repeat saturation after initial saturation) | 14/59 (24) |
| Park et al [21] | Clinic | 22/104 (21) |
| Ciatto et al [22] | Screening | 13/87 (15) |
| Catalona et al [23] | Clinic | 20/99 (20) |
| Durkan and Greene [24] | Clinic | 15/48 (31) |
| Total | – | 2121/9166 (23.1) |
The present urologic literature shows a trend to maximize PCa detection. This is sensible in a situation in which no clear guidance exists on how to best biopsy the prostate to diagnose PCa.
This last issue is the subject of this paper. The Rotterdam section of the ERSPC database provided the opportunity to study the clinical outcomes during an 11-yr follow-up period for PCa that was potentially missed at the first round of screening but was detected by screening 4 yr and 8 yr later or as interval cancer (IC).
2. Materials and methods
2.1. Patients and screening
A total of 42 376 men ages 55–74 were randomized to screening or to a control group between November 1993 and December 1999. During the first round, 19 970 men were screened (the study cohort). Initially biopsies were recommended for an abnormal digital rectal examination (DRE) or a prostate-specific antigen (PSA) elevation ≥4.0 ng/ml. From November 1997 on, DRE was abandoned as a screening test; sextant biopsies were recommended if PSA was ≥3.0 ng/ml. From June 1996 on, transrectal sextant biopsies were carried out in the more lateral peripheral zone [4].
In the meantime, data on the follow-up of the screened population of ERSPC Rotterdam became available for three rounds of screening and a complete inventory of IC for a follow-up period of 8–14 yr (mean: 11 yr). ICs are defined as any type of PCa detected clinically in between screens or after having reached the screening age limit of 75 yr.
All treatment decisions and the biopsies carried out in interval cases, as well as their pathologic evaluation, were done by regional health care providers. Progression-free survival (PFS) and PCa mortality were the end points.
2.2. Study design
Three comparative exploratory evaluations were carried out. First, we made an inventory of all cancers found in subsequent screening rounds or as IC in 3056 men with a negative biopsy at the initial screening. These cancers were assumed to be missed at the first screen. Their numbers and characteristics as well as their fates in terms of PFS and of death from PCa were then investigated and described.
Second, we compared the Kaplan-Meier projections [25] of PFS and PCa-specific survival for cancers detected during follow-up in men with initially negative biopsies, in men with no initial biopsy indication, and in those PCa detected during the first round of screening. These evaluations were considered exploratory, but statistical testing was still applied. The largest representative series of radical prostatectomies from the United States was used for reference [26].
Finally, the impact of “potentially missed PCa” on PCa mortality was considered at the level of the whole population of 19 970 screened participants.
2.3. Definitions
The TNM system of 1992 was used. Gleason grading was applied, but Anderson grading was used in some ICs diagnosed in regional hospitals [27].
Progression was defined as clinical evidence or a confirmed rise in the PSA level of 0.5 ng/ml.
Any PCa detected clinically or by opportunistic screening during the screen interval of 4 yr was regarded as IC. PCa mortality was determined by an independent committee [28].
2.4. Pathology evaluation
The evaluation of all pathologic specimens was done by one reference pathologist (TvdK) who reviewed all screen-detected PCa. There was no central review of the ICs.
2.5. Follow-up
Follow-up was by chart review in all PCa cases. IC and PCa in the control group were identified by linkage to the regional cancer registry. Deaths were identified in the whole study population by linking the ERSPC database to the database of the Central Bureau of Statistics of the Netherlands.
2.6. Statistical analysis
The statistical analysis was mainly based on numerical comparison and use of Kaplan-Meier estimates. Statistical testing was applied to the Kaplan-Meier curves by use of the log-rank test. A p-value ≤ 0.05 was considered significant. The SPSS v.15.0 statistical package was used (SPSS Inc., Chicago, IL, USA).
3. Results
The study population is shown in the flow diagram (Fig. 1). First-round PCa detection and PCa deaths are indicated. Numbers of biopsies, PCa found at screening, and numbers of ICs are indicated for men with initially negative biopsies (including potentially missed cancers) and the population of men who were not biopsied at the first screen.
01137-3/assets/gr1.jpg)
The available data allow a comparison of percentages of PCa deaths in relevant subgroups. In total during this 11-yr follow-up period, 70 of 19 970 (0.35%) men died of PCa. Most of these (n = 45 men) had their PCa detected at the first screen. Seven PCa deaths in 3056 men with initially negative biopsies amounted to 0.03%.
Table 3 reveals characteristics and outcomes of the 180 PCa detected at three screening rounds and over 12 yr as IC in the 3056 men who initially presented with a negative sextant biopsy and in those who did not have an initial biopsy indication. Of the 3056 men with initially negative biopsies, 26 (14.4%) progressed and 1 died of PCa (0.56%). Of the 107 ICs, 37 men were >75 yr at diagnosis, 23 (21.5%) showed progression, and 6 (5.6%) died of PCa.
Table 3 Number and characteristics of prostate cancer (PCa) detected 12 years after an initial negative sextant prostate biopsy in men biopsied with prostate-specific antigen (PSA) ≥4.0 ng/ml or abnormal digital rectal exam/transrectal ultrasound (protocol 5–9; round 1 plus round 1A) or PSA ≥3.0 (protocol 10; round 1) in the European Randomized Study of Screening for Prostate Cancer, Rotterdam section
| A (n) | Clinical stage (n, % of A) | Progression (n, % of A) | PCa death (n, % of A) | |
|---|---|---|---|---|
| – | T1A/T1B/T1C | Clinical + PSA | – | |
| Round 1 | ||||
| Men biopsied | 4133 | – | – | – |
| Men with negative biopsy | 3056 | – | – | – |
| PCa detected at interval 1 (year 0–4) | 26 | 17 (65.4) | 6 (23.1) | – |
| Round 2 | ||||
| Men died during first interval (all causes) | 97 | – | – | – |
| Men eligible | 2933 | – | – | – |
| Men actually screened* | 1647 | – | – | – |
| Men with biopsy indication | 1058 | – | – | – |
| Men biopsied | 993 | – | – | – |
| PCa detected | 120 | 72 (60.0) | 25 (20.8) | – |
| PCa detected at interval 2 (year 4–8) | 13 | 9 (69.2) | 3 (23.1) | 1 (7.7) |
| Men not screened/no biopsy | 1351 | – | – | – |
| PCa detected at interval 2 (year 4–8) | 40 | 23 (57.5) | 9 (22.5) | 4 (10.0) |
| Round 3 | ||||
| Men died during second interval (all causes) | 56 | – | – | – |
| Men not screened at second screening | 1286 | – | – | – |
| Men eligible | 1418 | – | – | – |
| Men actually screened | 762 | – | – | – |
| Men with biopsy indication | 449 | – | – | – |
| Men biopsied | 402 | – | – | – |
| PCa detected | 60 | 41 (68.3) | 1 (1.7) | 1 (1.7) |
| PCa detected at interval 3 (year 8–12) | 1 | 1 (100.0) | – | – |
| Men not screened/no biopsy | 703 | – | – | – |
| PCa detected at interval 3 (year 8–12) | 27 | 18 (66.6) | 5 (18.5) | 1 (3.7) |
| PCa detected at screening | 180 | 113 (62.8) | 26 (14.4) | 1 (0.6) |
| PCa detected at intervals | 107 | 68 (63.6) | 23 (21.5) | 6 (5.6) |
| Total PCa cases | 287 | 181 (63.1) | 49 (17.1) | 7 (2.4) |
A = number of men or number of PCa cases; T = trial.
*
Table 3 shows large groups of men who were eligible for screening but were not screened in the second and third screening rounds. Reasons for not undergoing screening in both segments, in order of highest to lowest frequency, included age >75 yr, refusal, and comorbidity. All men, however, irrespective of passing the age limit or of attending subsequent screenings, were followed by chart review and yearly linkage to the database of the Dutch cancer registry.
The raw data given in Table 3 on the fate of PCa found in men with negative initial biopsies and with no initial biopsy indication were further analyzed in Kaplan-Meier projections of PFS and PCa-specific survival with statistical testing.
Table 4a–c specifies details of fatal PCa in men with no initial biopsy indication or with no biopsy indication in screening rounds 2 and 3 and in those men with a negative initial biopsy.
Table 4 Detailed description of deadly prostate cancer (PCa) interval cases: (a) Men with no biopsy indication at initial screening (first interval: 0–4 years after initial screening); (b) men with no biopsy indication at initial screening (second interval: 4–8 years after initial screening); (c) men with a negative biopsy at initial screening (second interval (4–8 years) and third interval (8–12 years) after initial screening
| Initial screening | Repeat screening | Clinical detection | Screening result/classification | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Case No. | PSA | DRE | Age | Attend | PSA | T category | Grade* | Time after first screen, yr | Treatment** | Progression | Time from diagnosis to death, yr | |
| (a) | ||||||||||||
| Interval 1: 0–4 yr | ||||||||||||
| 1 | 2.8 | 1 | 68 | No | 2.8 | T2B | GS 6 (3 + 3) | 0.3 | RT | 1 | 3.5 | Recall after 1 yr/missed* |
| 2 | 42.2 | 9 | 73 | No | Unknown | T3C | G2 | 3.39 | EN | 1 | 2.1 | Refused further examination/missed |
| 3 | 1.0 | 9 | 74 | No | 51.5 | T4A | G3 | – | EN | 1 | 1.7 | Refused further examination/rapid progress |
| 4 | 42.0 | 9 | 64 | No | 42.0 | T3A | G2 | 0.25 | RT | 0 | 3.0 | Refused further examination/missed |
| 5 | 8.6 | 9 | 71 | No | 33.2 | T2C | G3 | 1.68 | EN | 1 | 3.5 | Refused further examination/missed rapid progress |
| 6 | 10.0 | 9 | 70 | No | 8.7 | T3A | G3 | 0.10 | EN | 1 | 0.7 | Refused further examination/missed |
| 7 | 2.6 | 9 | 62 | No | 762.0 | T1C | G3 | 2.30 | EN | 1 | 0.4 | Recall after 4 yr/rapid progress* |
| Case No. | PSA | DRE | Age | Repeat screening | Clinical detection | Screening result/classification | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Attend | PSA | T category | Grade* | Time after first screen, yr | Treatment** | Progression | Time from diagnosis to death, yr | |||||
| (b) | ||||||||||||
| Interval 2: 4–8 yr | ||||||||||||
| 8 | 2.1 | 0 | 74 | Too old | 5.2 | T1C | G3 | 6.8 | EN | 1 | 5.0 | Too old for repeat/missed* |
| 9 | 3.0 | 0 | 73 | Too old | 64.0 | T3A | G4 | 5.3 | EN | 1 | 1.3 | Too old for repeat/rapid progress* |
| 10 | 2.6 | 0 | 72 | Too old | 126.0 | T4A | GS 8 (4 + 4) | 7.5 | EN | 1 | 1.9 | Too old for repeat/rapid progress* |
| 11 | 2.2 | 0 | 59 | Yes | 3.7 | T2C | G1 | 7.8 | EN | 0 | 0.2 | Attended repeat/missed* |
| 12 | 1.0 | 0 | 56 | Moved | 30.0 | T4A | G2 | 4.5 | EN | 1 | 3.6 | Nonattender/missed |
| 13 | 2.2 | 0 | 72 | Too old | 1190 | T3C | GS 7 (3 + 4) | 7.1 | EN | 1 | 1.4 | Too old for repeat/missed* |
| 14 | 2.0 | 0 | 68 | At urologist | 46.0 | T4A | GS 7 (3 + 4) | 4.3 | EN | 1 | 1.4 | Repeat coincided with clinical diagnosis/missed* |
| Case No. | PSA | DRE | Age | Repeat screening | Clinical detection | Screening result/classification | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Attend | PSA | T category | Grade | Time after first screen, yr | Treatment | Progression | Time from diagnosis to death, yr | |||||
| (c) | ||||||||||||
| Interval 2: 4–8 yr | ||||||||||||
| 15 | 4.7 | 0 | 67 | Yes | 803.0 | T4A | G2 | 5.9 | EN | 1 | 1.5 | Missed*/rapid progress |
| 16 | 9.2 | 0 | 75 | Too old | 13.1 | T3C | GS 9 (4 + 5) | 5.8 | WW | 1 | 3.6 | Too old for repeat/missed* |
| 17 | 5.7 | 0 | 65 | Refused | 33.3 | T3B | GS 8 (4 + 4) | 4.0 | EN | 1 | 2.4 | Nonattender/rapid progress |
| 18 | 6.6 | 0 | 64 | Refused | 1080 | T2C | GS 9 (4 + 5) | 7.7 | EN | 1 | 2.4 | Nonattender/rapid progress |
| 19 | 22.0 | 0 | 62 | Refused | 55.0 | T2B | GS 7 (3 + 4) | 4.2 | RP | 1 | 5.0 | Nonattender/missed |
| Interval 3: 8–12 yr | ||||||||||||
| 20 | 1.3 | 1 | 59 | Refused | 164.0 | T3A | GS 7 (3 + 4) | 8.3 | EN | 1 | 0.5 | Nonattender/rapid progress |
*Screening failures: recall too late or above age cut-off of 74 yr.PSA = prostate-specific antigen; DRE = digital rectal examination (values: 0 = normal, 1 = abnormal, 9 = unknown); RT = radiotherapy; RP = radical prostatectomy; WW = watchful waiting; EN = endocrine treatment; GS = Gleason score; G = Anderson grade.
Fig. 2a shows the Kaplan-Meier curves starting at the time of randomization for biochemical or clinical PFS in men with PCa detected at the initial screen (1077 of 19 970 men, 299 [27.9%] progressive), those with initial negative biopsies (287 of 3056 men, 49 [17.1%] progressive), and of those PCa detected at later screens in men with no biopsy indication or refusal of biopsy at initial screen (867 of 15 837 men, 118 [13.6%] progressive); ICs are included. Comparisons of PFS after delayed detection are nonsignificant; those with PCa found at initial screening show significance in favor of delayed detection (p < 0.0001). In addition, the figure shows for comparison the PFS curve of 8265 radical prostatectomy cases, including all localized stages [26]. Fig. 2b gives similar projections but with separation of PFS in screen-detected and interval PCa. Compared with first-screen cancers and IC, men with PCa detected after initially negative biopsies showed significantly better PFS. Fig. 3a and b show similar Kaplan-Meier projections for PCa-specific survival using the same subgroups as in Fig. 2a and b. Fig. 4a and b present the same data as Fig. 3a and b, but now calculated from the time of diagnosis. Again, statistical testing showed no difference between the delayed detection groups. The comparison with PCa detected at initial screening was significant (p < 0.001). Other results of statistical testing are included in the legends.
01137-3/assets/gr2.jpg)
Fig. 2
Kaplan-Meier projections of progression-free survival after randomization for (a) prostate cancer (PCa) detected at the first screen (n = 1.077) after initial negative biopsy (n = 287) and with no initial biopsy indication (n = 867)* and (b) PCa detected at the first screen (n = 1.077) after initial negative biopsy and no initial biopsy indication but after subtraction of separately reported progression of interval cancers (n = 107 and n = 182, respectively).**
*p values of log-rank test: 2 versus 3, p = 0.218; 1 versus 2 + 3, p < 0.0001.
**p values of log-rank test: 1 versus 2.1 + 3.1, p = 0.002; 1 versus 2 + 3, p < 0.0001; 2.1 + 3.1 versus 2 + 3, p = 0.001.
01137-3/assets/gr3.jpg)
Fig. 3
Kaplan-Meier projections of prostate cancer (PCa)–specific survival after randomization: (a) PCa detected at the first screen (n = 1.077) after initial negative biopsy (n = 287) and with no initial biopsy indication (n = 867);* (b) PCa detected at the first screen (n = 1.077) and after initially negative biopsies and no initial biopsy indication but after subtraction of separately reported progression of interval cancers (n = 107 and n = 182, respectively).**
*p values of log-rank test: 2 versus 3, p = 0.718; 1 versus 2 + 3, p = 0.001.
**p values of log-rank test: 1 versus 2.1 + 3.1, p = 0.153; 1 versus 2 + 3, p < 0.0001; 2.1 + 3.1 versus 2 + 3, p < 0.0001.
01137-3/assets/gr4.jpg)
Fig. 4
Kaplan-Meier projections of prostate cancer-specific survival (a) as in Fig. 3a* and (b) as in Fig. 3b** but using the time of diagnosis as time 0.
*p values of log-rank test: 2 versus 3, p = 0.755; 1 versus 2 + 3, p = 0.492.
**p values of log-rank test: 1 versus 2.1 + 3.1, p < 0.0001; 1 versus 2 + 3, p = 0.018; 2.1 + 3.1 versus 2 + 3, p < 0.0001.
4. Discussion
As our literature review revealed, sextant biopsy, either classical or lateralized, will miss 23% or 19% of biopsy-detectable PCa, respectively. A recent review summarized the developments of biopsy techniques and their results during the period of the ERSPC study [29]. We cannot be certain that all cancers detected in the 3056 men with negative initial biopsies were actually present and thus were missed. Our assumption therefore is likely to overestimate the number of missed PCa, which strengthens our final conclusions.
What is the effect of missing PCa on progression and PCa mortality? The available long-term outcome information and the results of rescreening within the ERSPC database Rotterdam help provide an answer to the unresolved question: What would have been the outcome of patients who underwent lateralized sextant biopsies if potentially missed PCa had been detected immediately?
The Kaplan-Meier curves of PFS and PCa-specific survival show that PCa detected in the first screen have a poorer outcome than those detected by screening later on. The ICs have a strong negative impact on these outcomes. Our data on PFS are of the same order of magnitude as those reported from a large US cohort of predominantly screen-detected cases [26]. In the Kaplan-Meier curves, two different starting points were chosen. Using the time of randomization as time 0 (Fig. 2, and Fig. 3) is valid if one accepts the assumption that missed cancers were present at that time. Using time of diagnosis as time 0 allows direct comparison of outcomes. Obviously both approaches are sensitive to lead-time and length-time biases. Both biases move the time of diagnosis forward in comparison to the clinical diagnosis and, therefore, influence end points related to survival.
All comparisons show that the proportion of men with initially negative biopsies and unfavorable outcomes is small and compares favorably to the outcome of the study as a whole and to cases detected at the initial screen. Most unfavorable outcomes were seen in the men with an IC. Table 4 gives the background information for those PCa deaths occurring in cases missed at the first screen and in those who were not biopsied during the first round. Of the 20 PCa deaths, 14 occurred in men without initial biopsy indication and 6 in those 3056 men with initially negative biopsies. The last column in Table 4 gives the presumed reasons for death from PCa, despite participation in our screening study. Of those six IC with an initially negative biopsy who died of PCa, only two were considered to be “missed;” four refused biopsy. As Table 4 shows, 7 of 14 deadly ICs in men with no biopsy during the first screen were diagnosed clinically during the first 4-yr screening interval. Could these deaths have been prevented with a shorter interval?
Do sextant biopsies prevent most preventable disease progression and deaths from prostate cancer in a setting of repeated screening? Comparison of Fig. 2, Fig. 3, and Fig. 4 suggests that PFS and PCa-specific survival most frequently occur in men who present with an IC. Whether a shorter screen interval would prevent some or any of the unfavorable PFS and PCa-specific survival is an open question. As with any other cancer screening, some cancers will escape; which ones and what proportion is uncertain. In Schröder et al [1], PCa mortality in men who underwent screening was reduced by 27% at 9 yr of follow-up. In 73% of men in the screen arm who died of PCa, this could not be prevented. The results of our study show that men with potentially missed PCa have better outcomes than those with PCa identified at the first screen, and that their PFS and PCa-specific survival are comparable to men with no initial biopsy indication. These findings justify the conclusion that sextant biopsy, as an initial procedure, is safe in a setting of repeat screening.
Our study has a number of evident weaknesses. A direct comparison of the results of the sextant biopsies with immediate, multiple rebiopsies was not done; however, this may not be the best way to further evaluate our problem. A randomized trial would be preferable. The assumption that all PCa found at rescreening or during the intervals are missed at the first screen is probably wrong. This analysis was not preplanned but was conducted in a retrospective fashion. The authors realize that transperineal biopsies might have detected more cancers [30], and [31]. The change of the screening regimen and biopsy protocol during the ERSPC study may adversely influence our data. The use of the Anderson grading system in some interval cancers introduces some uncertainty.
Our study also has strong aspects. The biopsy procedures have continued to follow the ERSPC protocol and were not adapted to increasing clinical knowledge. Without this strategy, present evaluations would have been impossible. With an average 11-yr follow-up and two additional screens, most, if not all, aggressive PCa must have become identifiable by rescreening or surfaced as IC. Delayed detection is likely to lead to an overestimate of “potentially missed” PCa because many aggressive PCa that were undetectable at time 0 may only have become detectable at subsequent screens or as IC during the 11-yr follow-up. Aggressive PCa have a short lead time of approximately 5 yr, which is well within the range of our follow-up period [32]. This favors the main purpose of our study: to show that the screening regimen used will detect most aggressive PCa. More biopsies would detect more potentially indolent PCa.
Should we screen more aggressively? While the ERSPC study as a whole [1] showed the relative effects of screening in reducing PCa mortality by 20% in the intention-to-screen analysis, and by 30% for those men who in fact get screened [2], a very unfavorable number needed to treat (NNT) of 48 to save 1 PCa death at 9 yr of follow-up with respect to the control group resulted. While more aggressive screening may result in the detection of some aggressive PCa, which may be saved, most additional PCa are likely to be detected in the low PSA ranges, where nonaggressive PCa accumulate [33], and [34]. More detection of potentially indolent PCa will increase overdiagnosis, overtreatment, and the NNT. This will make general acceptance of screening for PCa more difficult, if not impossible.
The authors realize that their conclusions are not in line with European Association of Urology guidelines [35].
5. Conclusions
With repeat screening, a missed or delayed diagnosis does not lead to an excessive number of potentially incurable cases, progressive cases, or deaths due to PCa within the observation period of 11 yr. The rate of deaths due to PCa in those men with an initial negative biopsy of 0.03% compares favorably to the 0.35% rate of overall PCa mortality. Additionally, in the light of overdiagnosis and overtreatment inherent in the early detection of PCa, the usefulness of more extended biopsy schemes within this setting must be questioned. Sextant biopsy is not obsolete if repeat screening is applied.
Author contributions: Fritz H. Schröder had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Schröder.
Acquisition of data: Roobol, Wolters, van den Bergh, van Leeuwen.
Analysis and interpretation of data: Roobol, Schröder.
Drafting of the manuscript: Schröder.
Critical revision of the manuscript for important intellectual content: Bangma, van der Kwast, Schröder, Roobol, Wolters, van den Bergh, van Leeuwen.
Statistical analysis: Roobol.
Obtaining funding: Schröder.
Administrative, technical, or material support: None.
Supervision: Schröder.
Other (specify): None.
Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: This study is funded by grants from the Dutch Cancer Society (KWF 94-869, 98-1657, 2002-277, 2006-3518), the Netherlands Organisation for Health Research and Development (002822820, 22000106, 50-50110-98-311), the 6th Framework Program of the European Union (P-Mark: LSHC-CT-2004-503011), and Beckman Coulter Hybritech Inc. The sponsors were involved in the design and conduct of the study.
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Footnotes
Department of Urology, Erasmus MC, Rotterdam, The Netherlands
Corresponding author. Erasmus MC, University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Tel. +31 10 703 2240; Fax: +31 10 703 5315.
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