Bojanić Nebojša

Bumbaširević Uroš

Milojević Bogomir

Miočinović Ranko

Stephenson Andrew J.

Tulić Cane

Đorđević Miroslav L.

Vojnosanitetski pregled

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Vojnosanit Pregl 2013; 70(5): 501–503. VOJNOSANITETSKI PREGLED Strana 501Correspondence to: Andrew J Stephenson, Center for Urologic Oncology, Cleveland Clinic, 9500 Euclid Ave/Q10/-1, Cleveland, Ohio,44195 USA. Phone.: 0038 216 445 1062, Fax: 0038 216 636 4492. E-mail: stephea2@ccf.orgCURRENT TOPIC UDC: 616.65-07DOI: 10.2298/VSP1305501MOptimal use of prostate specific antigen for prostate cancer screeningOptimalna upotreba prostata specifiþnog antigena za otkrivanjekarcinoma prostateRanko Mioþinoviü*, Uroš Bumbašireviü†, Miroslav L. Djordjeviü‡, NebojšaBojaniü†, Bogomir Milojeviü†, Cane Tuliü†‡, Andrew J. Stephenson**Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA;†Clinic of Urology, Clinical Center of Serbia, Belgrade, Serbia, ‡Faculty of Medicine,University of Belgrade, Belgrade, SerbiaKey words:prostate neoplasms; prostate-specific antigen;diagnosis; risk assessment.Kljuÿne reÿi:prostata, neoplazme; prostata, specifiÿni antigen;dijagnoza; rizik, procena.IntroductionProstate cancer (PCa) and prostate specific antigen(PSA) screening have been the main focus of discussionsamong urologists and primary care physicians during the lastfew years 1. Ever since its introduction in the 1980s 2–4, PSAscreening was implemented as standard of care in many de-veloped countries, but without the supporting level I evi-dence to justify its initiation (mainly relating to reduction incancer-specific mortality). Several retrospective reports, suchas the Surveillance, Epidemiology, and End Results (SEER)database review suggested a significant decline in mortalityrates of 32.5% from PCa due to screening; the BaltimoreLongitudinal Study of Aging (BLSA) showed that PSA lev-els increased years before clinically detectable PCa and thatthis could lead to an effective early diagnosis and more ef-fective therapy 5. Similar findings were observed in the studyfrom Tyrol, Austria, where men from this particular regionhad a notable decrease in mortality after being screened withPSA in comparison to the rest of the country where PSAtesting was not freely available 6. However, in 2009 twolarge, randomized, prospective studies attempted to answerthis decade-long question: The Prostate, Lung, Colorectaland Ovarian Cancer screening trial (PLCO) from the UnitedStates which showed no benefit to screening 7, 8, and theEuropean Randomized Trial of Screening for Prostate Can-cer (ERSPC) which reported a 20% reduction in mortalityfrom PCa, but at the expense of 1,410 men having to un-dergo screening and additional 48 men to undergo treatmentin order to save 1 life 9–11. The latter results implied a signifi-cant overtreatment and overdiagnosis of clinically insignifi-cant cancers as a result of screening. Although survival ratesafter radical management of localized PCa are high, the riskof complications including urinary, sexual, and bowel dys-function is not negligible 12, 13.Based on these findings, the United States PreventiveServices Task Force (USPSTF) after careful review and bal-ance of the risks and benefits – mainly, problems of overdi-agnosis and over-treatment – recommended against a popu-lation-based screening program 14. The rationale for screen-ing after inconsistent results from these two large, random-ized trials coupled with the inherent PCa treatment compli-cations (including urinary, sexual, and bowel dysfunction)created a conflicting and confusing environment for theworld-wide treating physicians and their patients. Whilemany questions still remain unanswered, PSA (although animperfect test) continues to be the only tool we currentlyhave available to identify patients at higher risk of dyingfrom PCa.Adaption of new risk stratification strategies may be thesolution to minimize patient harms and offset the risk/benefitratio. In this report we provide evidence in support of earlyand targeted screening, earlier termination of screening, andprolongation of the screening interval to every 2–4 years.Early “targeted” screeningBased on the observational data from Sweden 15, PSAscreening when performed earlier in patient’s life seems toprovide strong prognostic risks relating to future develop-ment of clinically important PCa. Lilja et al. 15 reported that asingle PSA test obtained in the middle-aged men (ages 45–50) had a highly predictive risk of developing subsequentPCa. Specifically, they found that men with total PSA  0.5Strana 502 VOJNOSANITETSKI PREGLED Volumen 70, Broj 5Mioÿinoviý R, et al. Vojnosanit Pregl 2013; 70(5): 501–503.ng/mL had a cumulative low (10.5%) risk of developingclinically meaningful cancer by age of 75, those with PSAbetween 0.51 ng/mL and 1.0 ng/mL had a 2.5-fold increasedrisk, and men with PSA between 2.0–3.0 ng/mL were associ-ated with a 19-fold increased risk of developing cancer 15.Similarly, Vickers et al. 16 reported that men with PSA  1.0ng/mL at age 60 were highly unlikely to possess or developlife threatening PCa by age 85, and even lower risk (0.2%) ofdying from disease.These data are further supported by the findings ob-served by Stamey et al. 17 regarding correlation between PSAlevel at radical prostatectomy and final pathology. After acareful evaluation of almost 1,300 specimens, they docu-mented a strong association between the increasing PSA lev-els and prostate weight, or benign prostate hyperplasia(BPH), but not PCa 17. These observations imply that as menage and their prostates increase in size (mostly due to BPH),the PSA tends to loose its specificity for diagnosing PCa. Asa result, in the current PSA era the main “driver” for PSArise in older men seems to be mostly related to the amount ofBPH. Therefore, “targeted” screening with focus on youngerpopulation where BPH represents a minimal confoundershould improve the usefulness of PSA testing.Based on these findings, early PSA elevation couldidentify a cohort of men who would benefit from earlyscreening and/or preventive measures (pharmacological orlifestyle alterations) 18. Similarly, in those men without earlyPSA elevation screening could be potentially deferred untilage 50 and obtained less frequently 19. In cases with earlyPSA elevation, patients should only undergo biopsy if recog-nized indications for biopsy are present, such as PSA > 1.0ng/mL, PSA velocity (v) > 0.75 ng/mL/year, free: total PSA< 10%, and those with strong family history of early PCa.Early “termination” of screeningThere is strong evidence from previous reports thatscreening men for PCa in the PSA era should be stoppedearlier than current guidelines would suggest. According toa population-based study from the pre-PSA era by Albert-sen et al. 20, a significant number of PCa identified today(in the PSA era) would unlikely become clinically symp-tomatic over a patient’s lifetime. This was especially truefor well-differentiated tumors (Gleason 5–6), in which casethe majority of men died from the competing medical con-ditions during a 15–20 years follow-up 20. Interestingly,Draisma et al. 21 estimated the impact of PSA testing onlead-time of detecting clinically insignificant disease to be12 years for 55-year-old men, and estimated that approxi-mately half of the men ages 55–67 diagnosed with PCawould have non-important disease. This suggests thatscreening should probably be stopped for healthy men witha low-risk of developing PCa around age 60–65, given thelong lead-time and natural history of disease. As mentionedearlier, Vickers et al. 16 demonstrated in their study the riskof PCa death for men with PSA < 1.0 ng/mL at age 60 to benegligible. Therefore, termination of screening at later age(like 75) as American Urology Association (AUA) guide-lines recommend should be considered only in highly selectcases – those who are healthy and have a life expectancy of> 10–15 years.Risk stratification for prolonged screening intervalThe ERSPC 10 study, which clearly showed a reductionin PCa-specific mortality due to screening, was based on a2–4 year PSA screening interval. However, further subanaly-ses of the study seemed to support a potential for even fur-ther risk stratification and prolongation of screening time in-terval. For example, Roobol et al. 22 evaluated a group ofmen with initially low PSA (< 1ng/mL) who underwentevery 4–8 years screening interval and found only 0.23% riskof cancer diagnosis during the intervening visit. Anotherstudy showed a 0.5% risk of advanced disease and overall2.5% risk of prostate cancer at 15 years follow-up 23. On theother hand, van Leeuwen et al. 24 compared men from Goth-enburg screening cohort (2-year screening interval) to Rot-terdam cohort (4-year screening interval) and found thatmore frequent screening resulted in a higher proportion ofscreen-detected cancers (RR:1.18, p = 0.009). However,more frequent screening also led to increased incidence ofclinically insignificant (low-risk) PCa (RR: 1.46, p < 0.001).Interestingly, the Gothenburg cohort also had a lower inci-dence of advanced cancer during the last follow-up (RR:0.57, p = 0.048), which implied that more frequent screeningresulted into more effective way of eliminating high-risk PCafrom the population. Importantly, the effect on PCa-relatedmortality remained uncertain. This study implies that there isa certain population of men that may benefit from a morefrequent screening program, but an individualized approachaccording to patient risks would be the most optimal way ofscreening. Currently, there is no data that supports annualPSA screening for PCa – the best evidence is based onscreening every 4 years 10.ConclusionAccording to recent studies, PSA results obtained dur-ing an earlier age may be strongly predictive of long-termrisk of clinically important PCa, and as a result a risk-stratification approach should be considered in order tominimize over-diagnosis and overtreatment of this disease.The focus of screening should become on tumors withgreater malignant potential in the appropriate age population,instead of clinically insignificant tumors. Such an approachcould also reduce associated economic burden of treatingPCa in the present health-care system. Until new genomic-based markers are identified, PSA testing will continue toplay an important role in identifying patients with high-riskPCa and should not be abandoned.Volumen 70, Broj 5 VOJNOSANITETSKI PREGLED Strana 503Mioÿinoviý R, et al. Vojnosanit Pregl 2013; 70(5): 501–503.REFERENCES1. 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Optimal use of prostate specific antigen for prostate cancer screening

Optimal use of prostate specific antigen for prostate cancer screening

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