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Letters to the Editor NOT referring to a recent journal article Comment on the US Preventive Services Task Force’s Draft Recommendation on Screening for Prostate Cancer Only 3 yr from the date of its last publication , the US Preventive Services Task Force (USPSTF) has updated its recommendations for prostate cancer (PCa) screening. In the 2008 version, prostate-specific antigen (PSA) screening was discouraged for men aged 75 yr, whereas for younger men, there was no recommendation based on grade 1, as ‘‘the current evidence is considered . . . insufficient to assess the balance of benefits and harms’’ . In the current version, the USPSTF postulates a grade D recommendation regardless of age, thus discouraging PSA-based screening for PCa. The question is, what happened in the last 3 yr to justify this shift? The most important development was the publication of the results of the two prospective randomised trials designed to test the hypothesis that PSA-based screening would reduce PCa mortality. The European Randomised Study of Screening for Prostate Cancer (ERSPC) tested this in Europe , and the Prostate, Lung Colorectal, and Ovary (PLCO) study  tested it in the United States. The current evidence-based review by the USPSTF relies strongly on the Chou and colleagues’  interpretation of the results of these two trials. We disagree with the proposed recommendations. The major reason for this is that the interpretation by Chou et al is misleading and repeats biases similar to those in previous recently published meta-analyses [5,6]. The repetition of misleading analyses does not make them more correct. The quality and the results of a meta-analysis depend on the quality of the data of all pooled studies. This quality is insufficient for all but the ERSPC trial. Following is an analysis of why the other studies are sufficiently flawed that they should not be used to address the value of PSA screening. The results of both trials were published as preliminary analyses. The ERSPC had a median follow-up of 8.8 yr. The data were published because statistically significant PCa mortality difference was achieved at the third interim analysis in accordance with the planned trial analysis. PLCO reported 10-yr follow-up but with only 67% of mortality data available, with 98% complete follow-up at 7 yr. The scientific reasons for publication are unclear. These
follow-up durations are short relative to the natural history of PCa. For several reasons, even 10 yr of follow-up after randomisation is too short to draw conclusions about screening efficacy. Given the estimated mean lead time of 11.2 yr , large portions of cancers in the control population have not even emerged. Cancers detected at the first ‘‘prevalence’’ screening round were detected in part at more advanced stages and thus were too late for curative treatment . Untreated, most PCa patients will still be alive 10 yr after diagnosis; with treatment, this figure is significantly higher. The necessary follow-up time has to comprise both time from randomisation to diagnosis and time from diagnosis to death. The contemporary life expectancy of men aged 50 yr and 65 yr in Switzerland is 32 yr and 19 yr, respectively. An accurate estimate of the benefit of PSA-based screening requires longer follow-up, as demonstrated by the Go¨teborg randomised screening trial (the Swedish branch of the ERSPC). This group, which was the ERSPC cohort with the longest follow-up (5 yr longer than the ERSPC median), demonstrated PCa mortality reduction of 44% or 56% (unadjusted or adjusted for noncompliance, respectively) . The number needed to be PSA tested was 293, and the number of diagnosed cancers to save one PCa death was 12. Active surveillance was used in 42.1% of patients and could be maintained in 27.6% during follow-up. Only seven men had to be treated immediately (or nine over long-term follow-up) to prevent one cancer death. The additional 5-yr follow-up revealed dramatic improvement in screening efficacy. The USPSTF recommendation relied heavily on the PLCO trial results. PLCO was a very flawed trial compared to ERSPC. There are many reasons for this. The initially published assumptions for the power calculations  were not fulfilled: 37 000 men in each group would have been necessary to document a 27% mortality reduction in screening versus the control group with 90% compliance and contamination <20%. However, although compliance for PSA testing could be maintained between 85% and 89%, it was only at 30–40% for prostate biopsy (biopsy selfpayment or decision making with family physician) . At the same time, the contamination rate was 40–52% . This led to the protocol change in April 1995 excluding men having multiple PSA tests in the previous 3 yr .
0302-2838/$ – see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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Another major protocol change implemented in January 1996 was the decision to lower the eligible age limit to 55 (from 60). This second change also helped increase the initially low accrual rate. The power calculations were redone with the result that a minimum of 13 yr of follow-up after last randomisation in 2001 was required to compensate for those changes . The ‘‘missed’’ benefit of screening was also documented by the absence of an expected stage shift to lower stages and grades in the screening group compared to ERSPC (T3: 6.2% vs 4.5% [ERSPC: 20.5% vs 9.5%]; high Gleason score: 11.5% vs 8.4% [ERSPC: 13.4% vs 6.6%]). The generally lower rate of T3 and high Gleason scores in PLCO may be related to prescreening in 44%. Prescreening renders great difficulty in performing an adequately powered study in a country or region with a wide prevalence of PSA testing. This is especially true for PLCO because all power calculations were based on ‘‘pre-PSA’’ cancer mortality data from 1983 to 1987. This dwindling of statistical power, not documented in the paper , misleads the reader. Optimistically, the study power was reduced to 40–50%. Consequently, the risk of a type 2 error (a missed benefit) is excessively high. Given the methodological limitations of the PLCO trial, pooling these trials in a meta-analysis (eg, Ilic et al. ) risks diluting the true effect of screening. With regard to the excessively high risk of type 2 error, we feel that this is an important point that is often not sufficiently explained. Simplistically speaking, if the power of a trial is at 40–50%, it means that if we perform 100 identical trials and the effect is true (ie, the PSAbased screening truly reduces PCa mortality by 20%—the basic assumption of the PLCO study under ‘‘ideal’’ conditions), then only 40–50 of these hypothetical trials will demonstrate this effect in a statistically significant manner; the rest will not. The maintenance of statistical power throughout the whole study period is the crucial problem in executing such a long-term trial. As the PLCO researchers stated themselves, ‘‘A high power of at least 90% is mandatory to yield a meaningful negative result, should that happen, and to achieve a high level of scientific validity because a trial of this magnitude addressing these questions is not likely to be repeated’’ . Another important detail is that the PLCO researchers used (for pragmatic reasons) one-sided hypothesis testing, thus looking only for screening benefit, in contrast with ERSPC, which used more stringent two-sided hypothesis testing, thus also testing for screening harms. In 2011, PLCO reported mortality benefit with a promising number needed to treat of only five to save one PCa death in healthy young men being screened , supporting the results of the Go¨teborg study . However, this post hoc subgroup analysis should be interpreted with caution . For comparison, the ERSPC trial randomised 162 243 European men into the ‘‘core-age group’’ of 55–69. This age criterion was predefined per the study protocol and never changed. As for this group, it had a power of 86% to show a statistically significant difference of 25% in PCa mortality with follow-up through 2008, assuming a 20% contamination rate . Compliance with PSA testing was 82% and,
importantly, compliance with prostate biopsy was high, at 86%, whereas contamination reached 15% (below the assumptions). At least, the power of the ERSPC trial was maintained. The strength of ERSPC as a multicentre trial has been underscored, as it could have been shown that the results develop in the same direction and will not change significantly if any centre is removed, with the exception of the Swedish branch, where the p value for other centres increased to 0.06 , pinpointing the need for longer follow-up for the trial as a whole. The USPSTF decision also relies heavily on the metaanalysis of Ilic et al. . This Cochrane review included the Quebec, Norrko¨ping, and Stockholm screening studies as well as PLCO and ERSPC. The Quebec trial  has wellknown severe methodological flaws that have been scrutinised extensively elsewhere [18,19]. The Norrko¨ping study  is based mainly on digital rectal exam (DRE; starting in 1987). PSA was added late in the course of the study (1996). Consequently, localised tumours were present in only 56% of the cases, far from the expected stage shift of a PSA-based screening study. The cumulative incidence of 5.7% was low, given the 12-yr duration of the study. The study was not powered to provide definite evidence supporting or rejecting screening as a method for reducing PCa mortality. Notwithstanding these flaws, Ilic et al included these data in the pool, severely jeopardising the quality of this meta-analysis. The data of the Stockholm study  have the same flaw. The study was DRE driven (62 of 65 cancers were detected by DRE). Only 11 of 65 cancers received curative treatment. More PCa was diagnosed in the control arm than in the screening arm. The study is of little value in addressing the USPSTF question. Although ERSPC did show a benefit, the quantification of benefits and harms of screening in the study is premature. The intent of the first publication was to document a small but significant benefit after 9 yr—earlier than expected. The 11- and 13-yr follow-up data are required to assess the benefit, similar to the 14-yr follow-up of the Go¨teborg study. In addition, the 31% risk reduction of metastatic disease documents another beneficial screening effect that should be considered . The USPSTF did not address contemporary trends in PCa mortality in the United States and elsewhere. The Surveillance Epidemiology and End Results data from Jemal et al.  and the modelling exercise of Etzoni et al.  showing significant PCa mortality reduction related to PSA screening are not included in the analysis. A key component of the USPSTF decision relates to the risk of overtreatment of indolent PCa. Active surveillance has been increasingly embraced as a solution to the problem of overtreatment. More than 3000 patients managed prospectively by active surveillance have been reported in the published literature , and this approach is becoming increasingly adopted throughout the Western world. This means that aggressive treatment can be restricted to those patients with intermediate- and high-risk PCa, and the number needed to treat is likely to fall even further.
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Unfortunately, active surveillance, or selective therapy for favourable risk disease, has not been widely embraced in the United States. According to the most recent data available, 90% of men with low-risk PCa receive radical therapy . The USPSTF position on overtreatment is valid. However, this recommendation reflects the US situation and should not be interpreted as applying to PSA screening in constituencies for which active surveillance for low-risk disease is embraced. In conclusion, a recommendation against PSA-based screening, particularly for men <65 yr of age with a life expectancy between 19 yr and 32 yr, on the basis of studies with <10 yr of follow-up is premature. Longerterm data (ie, the Go¨teborg study) document mortality reduction of 50% and a number needed to treat as low as seven. Overtreatment can be reduced by active surveillance. The USPSTF has ‘‘thrown the baby out with the bathwater.’’ PSA, used intelligently (as suggested by Schroder ), has the potential to reduce PCa mortality at an acceptable cost.
 Prorok PC, Andriole GL, Bresalier RS, et al. Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Control Clin Trials 2000;21:273S–9S.  Grubb III RL, Pinsky PF, Greenlee RT, et al. Prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian cancer screening trial: update on ﬁndings from the initial four rounds of screening in a randomized trial. BJU Int 2008;102:1524–30.  Simpson NK, Johnson CC, Ogden SL, et al. Recruitment strategies in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial: the ﬁrst six years. Control Clin Trials 2000;21:356S–78S.  Gohagan JK, Prorok PC, Hayes RB, Kramer BS. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial of the National Cancer Institute: history, organization, and status. Control Clin Trials 2000;21:251S–72S.  Crawford ED, Grubb III R, Black A, et al. Comorbidity and mortality results from a randomized prostate cancer screening trial. J Clin Oncol 2011;29:355–61.  Bach PB, Vickers AJ. Do the data support the comorbidity hypothesis for the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial results? J Clin Oncol 2011;29:e387, author reply e388–9.  de Koning HJ, Liem MK, Baan CA, Boer R, Schroder FH, Alexander FE. Prostate cancer mortality reduction by screening: power and time frame with complete enrollment in the European Randomised
Conﬂicts of interest: Maciej Kwiatkowski, Franz Recker, and Jonas Hugosson are members of the European Randomised Study of Screening
Screening for Prostate Cancer (ERSPC) trial. Int J Cancer 2002;98: 268–73.
for Prostate Cancer (ERSPC) scientiﬁc committee and are principal
 Labrie F, Candas B, Dupont A, et al. Screening decreases prostate
investigators of the Swiss (MK, FR) and Swedish (JH) centres of the
cancer death: ﬁrst analysis of the 1988 Quebec prospective ran-
ERSPC. Laurence Klotz is principal investigator of several studies of active surveillance treatment for low-risk PCa.
domized controlled trial. Prostate 1999;38:83–91.  Boer R, Schroder FH. Quebec randomized controlled trial on prostate cancer screening shows no evidence for mortality reduction.
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EUROPEAN UROLOGY 61 (2012) 851–856
Maciej Kwiatkowskia,* Laurence Klotzb
*Corresponding author. Kantonsspital Aarau AG, Urologische Klinik,
Tel. +41 62 838 47 47; Fax: +41 62 838 4753.
E-mail address: [email protected]
Tellstrasse, Aarau, CH-5001, Switzerland
Department of Urology, Kantonsspital Aarau, Aarau,
January 16, 2012
Published online ahead of print on January 24, 2012
Division of Urology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada
Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy
at University of Go¨teborg, Go¨teborg, Sweden
Death Certificates Are Valid for the Determination of Cause of Death in Patients With Upper and Lower Tract Urothelial Carcinoma Accurate appraisal of cause of death (COD) is critically important for determining correct cause-specific survival in cancer patients. Death certificates are used for assessment of COD in case control , cohort outcomes , and occupational mortality studies . Likewise, large data sets, such as the Surveillance Epidemiology and End Results program, and tumor registries rely on death certificates to assign COD [4,5]. However, this method may become inaccurate (1) when patients get older, (2) when patients have serious comorbidities associated with a risk of dying of other causes [6,7], or (3) when cancer patients are long-term survivors. Urothelial cancer (UC) is the second most common genitourinary cancer in the United States and represents an important cause of morbidity and mortality . UC is generally a disease of the elderly, who have considerable comorbidities [9,10]. Although meticulous review of medical records has been shown to reliably ascertain COD in other urologic diseases such as prostate cancer (PCa) [5,11], the validity of death certificates for UC patients remains mainly uninvestigated. Therefore, we assessed whether the underlying COD on death certificates for men with UC agreed with an independent review of medical records for UC patients. This was an institutional review board–approved study. In our institutional database, we identified a sample of 137 patients with UC of the urinary bladder (UCB) treated with radical cystectomy and 62 patients with upper tract UC (UTUC) treated with radical nephroureterectomy who died at one tertiary care center during follow-up. Two trained
urologists who were blinded to the COD assigned by the death certificate used a standardized data extraction form to independently review medical records and evaluate clinical course before death and effect of comorbidities. COD was assigned to one of three prospectively defined categories: (1) related to UCB or UTUC, (2) unrelated to UCB or UTUC, or (3) uncertain. Cohen’s k test was used to evaluate the agreement between both raters. Statistical analyses were performed with SPSS 17 (IBM Corp., Armonk, NY, USA). Death certificates were available for 119 UCB patients (86.9%) and 54 UTUC patients (87.1%). Median age was 67 yr (interquartile range [IQR]: 13) for UCB patients and 69 yr (IQR: 15) for UTUC patients. Both urologists agreed on the underlying COD in 166 of 173 UC patients (96%); consensus was reached on the COD of the remaining 7 patients. The comparison of underlying COD when assigned by death certificate and clinician assessment of medical records is shown in Table 1. Overall agreement was 96.1% for UCB patients who died of their disease and 92.5% for those patients who died of causes other than UCB (k = 0.89; p < 0.001). In UTUC patients, agreement was 93.9% and 85.0% in patients dying of disease and those patients dying of other causes, respectively (k = 0.80; p < 0.001). The agreement between the death certificate COD and the medical record review consensus assessment of COD was higher for UCB (92.4%) than for UTUC (88.9%). The UCB patients who died of their disease but were misclassified as dead from other cause by death certificate died of metastatic complications of UCB: One patient was misclassified as having a brain tumor, whereas he had brain metastasis of UCB; one patient had a pulmonary embolism due to tumor-induced coagulopathy; and one patient had
Table 1 – Comparison of underlying cause of death in 119 patients with urothelial carcinoma of the bladder and 54 patients with upper tract urothelial carcinoma patients according to death certificate and consensus assessment of medical records Consensus assessment of underlying COD Death certiﬁcate underlying COD UCB Other COD
Death certiﬁcate underlying COD UTUC Other COD
Related to UCB, no. (%)
Unrelated to UCB, no. (%)
75 (96.1) 3 (7.5)
3 (3.9) 38 (92.5)
Related to UTUC, no. (%)
Unrelated to UTUC, no. (%)
31 (93.9) 3 (15.0)
3 (6.1) 17 (85.0)
COD = cause of death; UCB = urothelial carcinoma of the bladder; UTUC = upper tract urothelial carcinoma.