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improve the predictive accuracy of a single PSA measurement 15 years or more before cancer diagnosis in a large, representative, unscreened population. J Clin Oncol 2008; 26: 835.
26. Djavan B, Ravery V, Zlotta A et al: Prospective evaluation of prostate cancer detected on biopsies 1, 2, 3 and 4: when should we stop? J Urol 2001; 166: 1679.
36. Ostrander EA and Udler MS: The role of the BRCA2 gene in susceptibility to prostate cancer revisited. Cancer Epidemiol Biomarkers Prev 2008; 17: 1843.
17. Thompson IM, Ankerst DP, Chi C et al: Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst 2006; 98: 529.
27. Andriole G, Bostwick D, Brawley O et al: Chemoprevention of prostate cancer in men at high risk: rationale and design of the reduction by dutasteride of prostate cancer events (REDUCE) trial. J Urol 2004; 172: 1314.
37. Bostwick DG and Qian J: High-grade prostatic intraepithelial neoplasia. Mod Pathol 2004; 17: 360.
18. Etzioni RD, Ankerst DP, Weiss NS et al: Is prostate-specific antigen velocity useful in early detection of prostate cancer? A critical appraisal of the evidence. J Natl Cancer Inst 2007; 99: 1510. 19. Schröder FH and Kattan MW: The comparability of models for predicting the risk of a positive prostate biopsy with prostate-specific antigen alone: a systematic review. Eur Urol 2008; 54: 274. 20. Bostwick DG, Burke HB, Djakiew D et al: Human prostate cancer risk factors. Cancer 2004; 101: 2371. 21. Bostwick DG, Qian J, Civantos F et al: Does finasteride alter the pathology of the prostate and cancer grading? Clin Prostate Cancer 2004; 2: 228. 22. Canby-Hagino E, Hernandez J, Brand TC et al: Prostate cancer risk with positive family history, normal prostate examination findings, and PSA less than 4.0 ng/ml. Urology 2007; 70: 748. 23. Roobol MJ, Schroder FH and Kranse R: A comparison of first and repeat (four years later) prostate cancer screening in a randomized cohort of a symptomatic men aged 55-75 years using a biopsy indication of 3.0 ng/ml (results of ERSPC, Rotterdam). Prostate 2006; 66: 604.
28. Steuber T, Vickers A, Haese A et al: Free PSA isoforms and intact and cleaved forms of urokinase plasminogen activator receptor in serum improve selection of patients for prostate cancer biopsy. Int J Cancer 2007; 120: 1499. 29. Catalona WJ, Partin AW, Slawin KM et al: Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 1998; 279: 1542. 30. Eggener SE, Yossepowitch O, Roehl KA et al: Relationship of prostate-specific antigen velocity to histologic findings in a prostate cancer screening program. Urology 2008; 71: 1016. 31. Carter HB, Morrell CH, Pearson JD et al: Estimation of prostatic growth using serial prostatespecific antigen measurements in men with and without prostate disease. Cancer Res 1992; 52: 3323. 32. Roobol M: (I) Re: prostate specific antigen velocity in men with total prostate specific antigen less than 4 ng/ml. Eur Urol 2008; 53: 852.
38. Bostwick DG and Meiers I: Atypical small acinar proliferation in the prostate: clinical significance in 2006. Arch Pathol Lab Med 2006; 130: 952. 39. Epstein JI: What’s new in prostate cancer disease assessment in 2006? Curr Opin Urol 2006; 16: 146. 40. Epstein JI and Herawi M: Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol 2006; 175: 820. 41. Lilja H, Ulmert D and Vickers AJ: Prostate-specific antigen and prostate cancer: prediction, detection and monitoring. Nat Rev Cancer 2008; 8: 268. 42. Vickers AJ, Ulmert D, Serio AM et al: The predictive value of prostate cancer biomarkers depends on age and time to diagnosis: towards a biologically-based screening strategy. Int J Cancer 2007; 121: 2212. 43. Gosselaar C, Roobol MJ, van den Bergh RC et al: Digital rectal examination and the diagnosis of prostate cancer—a study based on 8 years and three screenings within the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam. Eur Urol 2009; 55: 139.
33. Roobol M: (II) Re: prostate specific antigen velocity in men with total prostate specific antigen less than 4 ng/ml. Eur Urol 2008; 53: 854.
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EDITORIAL COMMENTS Routine prostate cancer screening remains highly controversial. Unfortunately the recently reported interim results of ongoing prospective screening trials have not resolved the issue, although they do suggest that significant over diagnosis occurs with annual PSA based screening.1,2 Whether or not the studies ultimately demonstrate a decrease in prostate cancer specific mortality, it is likely the net cost and morbidity of routine screening may not be justified, and a more directed approach will be needed in the future. Urologists have generally favored PSA screening over no screening, and we usually frame the question in the here and now. Does the patient today
have a likelihood of prostate cancer based on their current PSA value, their ethnicity, their family history, their examination? Does this man need a prostate biopsy? While we may consider some dynamic aspects of data, perhaps factoring in PSA change and velocity to answer those questions, the assessment is still static and we do not usually have a long-term perspective when evaluating a man for prostate cancer. If the current perceived risk is low, biopsy is deferred and the patient is usually asked to return in a year, with the process repeated anew at the next visit continued on indefinitely. The authors of this review highlight the ability to estimate the future development of prostate cancer
IDENTIFICATION OF INCREASED PROSTATE CANCER RISK
using the same information that we already apply in estimating current risk. This is an important and timely concept, and by stratifying patients regarding long-term risk for prostate cancer, we can tailor the intensity of screening to the individual estimated risk. Instead of the current practice of a single protocol where all men are screened in essentially the same manner regardless of long-term estimated risk, we can identify men with different estimated risks for prostate cancer, and establish and adopt more or less intense surveillance schedules for these different groups of men as appropriate. If there is a benefit from prostate cancer screening, it will most likely need to be optimized to justify its overall cost. While this is an attractive concept, there are certain issues regarding its immediate clinical implementation. Although men at increased long-term risk for prostate cancer can be identified and the authors suggest considering heightened surveillance for these men, further over diagnosis and overtreatment of prostate cancer is the most likely result. For these higher risk men additional biomarkers are needed to
improve the prediction not only for the risk of prostate cancer, but for aggressive and high grade disease that truly warrants intervention. For men with below average longitudinal risk, eg less than 5% 4-year risk (fig. 1), perhaps less intensive followup is sufficient instead of annual surveillance, and this could lower the burden and cost for men in whom regular screening might be unnecessary. This less intensive surveillance demands additional prospective validation to confirm the age specific PSA threshold that can allow for a greater screening interval, but appears promising based on the evidence of existing longitudinal studies. Importantly the development of additional molecular and biomarkers are expected to improve the predictive accuracy of future risk estimates, which should only serve to strengthen the rationale and benefit of a tailored approach to prostate cancer screening. David Y. T. Chen Department of Surgical Oncology Section of Urologic Oncology Fox Chase Cancer Center Philadelphia, Pennsylvania
REFERENCES 1. Andriole GL, Crawford ED, Grubb RL 3rd et al: Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009; 360: 1310. 2. Schroder FH, Hugosson J, Roobol MJ et al: Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009; 360: 1320.
This review provides a useful reference for determining levels of risk of a prostate cancer diagnosis for men of screening age. By stratifying patients into 3 categories the likelihood of harboring and subsequently contracting the condition can be predicted. In an evidence-based approach analyzing various adaptations of PSA together with clinical and histological parameters, tPSA was rated as most predictive. Results from genetic and molecular markers such as BRCA mutations1,2 and PCA3 testing of postprostatic massage urine3 are not included in this review, as they have not yet stood the test of time.
Clearly no single marker appears able to clearly define patients who do and do not have prostate cancer, with combinations reported to be more effective. Consequently reliance will be placed increasingly on predictive tools for interpretation and serum PSA can be expected to continue to have a central role in these analyses. Robert A. Gardiner University of Queensland Centre for Clinical Research & Department of Urology Royal Brisbane & Women’s Hospital Brisbane, Queensland, Australia
REFERENCES 1. Willems AJ, Dawson SJ, Samaratunga H et al: Loss of heterozygosity at the BRCA2 locus detected by multiplex ligation-dependent probe amplification is common in prostate cancers from men with a germline BRCA2 mutation. Clin Cancer Res 2008; 14: 2953.
2. Mitra A, Fisher C, Foster CS et al: Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype. Br J Cancer 2008; 98: 502.
3. Hessels D and Schalken JA: The use of PCA3 in the diagnosis of prostate cancer. Nat Rev Urol 2009; 6: 255.