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e d i t o r i a l PSA based screening reduces the rate of prostate cancer death by 20% A uthors H. Van Poppel, C. Bangma Key words Prostate cancer, PSA screening Summary Recently The New England Journal of Medicine recently published two original articles on screening for prostate cancer. Both were randomized studies, one performed in the US and Introduction The US study, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial ran from 1993 through 2001 in 10 US study centres. About 67,700 men were randomized to receive either annual screening or usual care and a PSA of ≥ 4.0ng/ ml indicated prostate biopsy. After 7 to 10 years of follow up, the rate of death from prostate cancer did not differ significantly between the 2 study arms. The European Randomized study of Screening for Prostate Cancer (ERSPC) randomized more than 160,000 men, aged 55 to 69 years. Prostate biopsy was performed when the PSA was ≥ 3.0ng/ml and the study showed a clearly reduced rate of death from prostate cancer by 20%. Discussion In the same journal both articles were discussed by Dr. M.J. Barry under the title: “Screening for prostate cancer: the controversy that refuses to die”.3 Since, many experts have attempted to bring correct information in the lay press using the stronger or weaker points of both studies to defend or destroy the usefulness of PSA based prostate cancer screening. This is obviously bringing more confusion to our healthy male population. On the 3rd of April, the American Urological Association (AUA), reacted on the internet by saying that these studies cannot lead to the conclusion that PSA screening should be abandoned and that PSA testing remains B E L G I A N J O U R N A L O F M E D I C A L published by Andriole et al the other performed in Europe and published by Schröder et al.1,2 Both studies yielded conflicting data concerning PSA screening and prostate cancer drugs. (BJMO 2009;Vol 3;5:209-211) a valuable screening tool and should be appropriately offered to men. “Prior to the use of the PSA test, tumors were found mostly in advanced, and less treatable, stages giving patients far fewer options for treatment. It is the opinion of the AUA that the PSA test is a valuable screening tool that saves lives and men with concerns about elevated PSA scores should consult their urologist about next steps.” Prof. Dr. Chris Bangma, chairman of the Department of Urology at the university of Rotterdam (successor of Prof. F.H. Schröder, first author of the ERSPC study), therefore wrote to the general practitioners and urologists in the Netherlands about what has become a Europe vs. US debate. In terms of a football game one seems to be at a 1-1 draw and this is indeed translated in the lay press as a continuity in the doubt about reduced mortality by PSA screening. Therefore some clarification is needed. What are the conditions for a good screening study on cancer mortality? Mainly, there are four points that are critically important to successfully run a randomized study in the population: 1.Clean inclusion: at the start of the study the participants may not have been examined for the disease under study. 2.Good compliance: sufficient number of participants are needed that strictly follow the complete protocol. 3.Few contamination: the participants in each O N C O L O G Y vol. 3 issue 5 - 2009 209 e d i t o r i a l Key messages for clinical practice 1. The ERSPC study has undoubtedly shown that PSA screening and prostate biopsy at PSA ≥ 3,0ng/ml reduces prostate cancer mortality by 20%. 2.The PLCO study, in which the rate of death from prostate cancer did not differ significantly between patients who underwent yearly PSA screening and patients who underwent usual care after 7 to 10 years of follow up, is qualitatively to poor to ever be able to show a difference, even with a longer follow up time. 3.Many experts today will look at PSA velocity in younger patients and consider age related PSA values instead of working with fixed PSA thresholds to trigger prostate biopsies. arm need to comply with the protocol and not switch to the other study arm. 4.Long follow up: participants need to be followed up sufficiently long in order to reach the aimed endpoint. In the PLCO study, these 4 points are under considerable threat: 1.At initiation, there was no exclusion of participants that already had a PSA testing before. It is therefore possible that the participating population was already cleaned from a number of prostate cancers or cleaned from men with a very low PSA that found the need of a second screening superfluous. In the PCLO study 43 % of men had already undergone 1 or more PSA testings before inclusion in the study. In the ERSPC trial men were not allowed to participate when they had previously undergone PSA testing. 2.In the PCLO study, about 40% of men with a PSA ≥ 4.0ng/ml followed the protocol and underwent a biopsy as prescribed. So there was protocol violation in 60% of the cases. The compliance in the ERSPC protocol was about 90%. 3.In both randomized studies men in the control arm should not undergo PSA testing. In the PLCO study 52% of the patients in the control arm still got PSA testing, while in the screening arm this was 85%. Understandably this high rate of contamination in the control group, because of an abuse of PSA testing in the US, made it about impossible for PLCO with 77,000 participants to ever give an answer to the question whether prostate cancer mortality is reduced by PSA testing. With a difference in PSA testing of only 33% between the 2 arms in the PLCO study this could have been foreseen. In 210 vol. 3 issue 5 - 2009 the ERSPC study this difference is about 80%. When the European study was designed and the power calculation was done the fact of contamination was already taken into account. Because of a much lower PSA use in Europe in the initial phase of the ERSPC trial, this low level of contamination had no influence on the outcome of the trial. 4.The PLCO study has a follow up of only 7 years and this is too short to show a difference in mortality. The authors of the PLCO study also acknowledge this fact. Because of larger numbers in the European study this difference could indeed be shown after 9 years. All the above mentioned reasons are the main causes why the PLCO study could not come to a positive difference but also shows that the study is qualitatively poor to ever be able to show a difference, even with longer follow up. For the European researchers it is clear that the PLCO study cannot contribute to a solution of the question whether screening can decrease prostate cancer mortality. More importantly the analysis of quality of life gain by the reduced cancer specific mortality will be most important. Indeed, despite the fact that the screening effect (prevent one cancer death by screening 1,400 men) is comparable with effects described for screening in breast and colon cancer, the over-diagnosis of insignificant tumors is much higher for prostate cancer. Over-diagnosis is not a correct wording since a cancer that is present cannot be ‘over’diagnosed. The real problem is that a certain amount of insignificant cancers are still treated by radical prostatectomy, external beam radiotherapy or interstitial radiotherapy, while if they were left untreated it is B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y very likely that they would never harm the patient. If this problem of overtreatment would not exist, nobody would continue to discuss the fact whether PSA based prostate cancer screening is useful. The ERSPC study has undoubtedly shown that PSA screening and prostate biopsy at PSA ≥ 3.0ng/ml reduces prostate cancer mortality by 1/5. Many urologists today will not any longer use a certain PSA cut off to trigger prostate biopsies. Many experts today will look at PSA velocity in younger patients and consider age related PSA values. If this would have been done in the screening study, the reduction in prostate cancer mortality would even have been more pronounced. Prostate cancer research should now focus on how to distinguish significant and insignificant cancers, give more space to active surveillance in order to differentiate between indolent and life threatening cancers. Once this issue is solved, the controversy about prostate cancer screening will have died. References 1. GL Andriole, RL Grubb, SS Buys, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl Med 2009;360;1310-1319. 2. FH Schröder, J Hugosson, MJ Roobol, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009;360;1320-1328. 3. MJ Barry. Screening for prostate cancer – The controversy that refuses to die. N Engl J Med 2009;360;1351-1354. Correspondence address Authors: H. Van Poppel 1 and C. Bangma 2 1 University Hospitals Leuven, Department of Urology, Herestraat 49, 3000 Leuven, Belgium; 2 Erasmus MC University Medical Centre Rotterdam, Dept. of Urology, Rotterdam, The Netherlands Please send all correspondence to: Prof. Dr. H. Van Poppel Department of Urology University hospitals Leuven Herestraat 49 3000 Leuven Belgium [email protected] Conflicts of interest: the authors have nothing to disclose and indicate no potential conflicts of interest. For you and your patient: Multidisciplinary National Cancer Guidelines, established by the College of Oncology in collaboration with the KCE are accessible at : www.guidelinescancer.be www.richtlijnenkanker.be www.recommandationscancer.be B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y vol. 3 issue 5 - 2009 211