Prostate Cancer

Reviewing the Literature

RIU0338_05-15.qxd 5/15/07 1:49 PM Page 91 Prostate Cancer Prostate Cancer Prostate-Cancer Risk Stratification via Early PSA Testing Reviewed by Danil V. Makarov, MD, Alan W. Partin, MD, PhD The James Buchanan Brady Urological Institute, Department of Urology, The Johns Hopkins Medical Institutions and Hospital, Baltimore, MD [Rev Urol. 2007;9(2):91-92] © 2007 MedReviews, LLC he American Cancer Society (ACS)1 and the American Urologic Association (AUA)2 both recommend initiation of prostate-specific antigen (PSA) screening in the 40s (the ACS recommends age 45 and the AUA age 40) for African American men and men with a family history of PSA, and age 50 for all other men with at least a 10-year life expectancy. The National Comprehensive Cancer Network (NCCN) recommends obtaining a baseline PSA level for all men in their 40s.3 PSA screening remains controversial, as many critics point out that it has never demonstrated a survival advantage. Many groups, therefore, do not recommend PSA screening at all. A burgeoning body of literature now deals with the long-term predictions that can be made with PSA values obtained from patients while in their 40s.4,5 Two prominent articles on early risk stratification have been published recently. T Long-Term Prediction of Prostate Cancer up to 25 Years Before Diagnosis of Prostate Cancer Using Prostate Kallikreins Measured at Age 44 to 50 Years Lilja H, Ulmert D, Björk T, et al. J Clin Oncol. 2007;25:431-436 Lilja and colleagues have confirmed several previous observations that PSA measured many years prior to diagnosis has predictive capability. More than simply looking at total PSA, however, the group examined other PSA isoforms, human kallikrein 2 (hK2), and 90 lifestyle, anthropometric, biochemical, and medical history variables. The group studied a cohort of men between ages 33 and 49 years enrolled in a cardiovascular study between the years 1974 and 1986 in Malmö, Sweden. Of 21,777 men (74% of Malmö’s male population) registered in the study, 498 were diagnosed with prostate cancer and 462 had archived plasma available for the analysis of hK2, free PSA, and total PSA (tPSA). Significantly, plasma samples were stored at 20°C and measured using an assay differing 13% from World Health Organization (WHO) calibration standards, both factors compromising measurement of the absolute PSA. These men were then matched (approximately 1:3) with 1222 control subjects without diagnosed prostate cancer. The median time between serum collection and prostate cancer diagnosis was 18 years (interquartile range, 1520). Needle biopsy demonstrated that 37% of patients were WHO grade 1, 38% were grade 2, and 25% were grade 3. Differing from a US cohort, only 24% were clinical stage T1 at presentation, whereas 38% were T2 and 38% were T3 or T4. On univariate analysis, hK2 and all PSA isoforms were strongly associated with prostate cancer, and all had strong interactions. Therefore, only tPSA was left in the model. Although 3 of the 90 anthropometric, lifestyle, biochemical, and medical history variables measured were predictive on univariate analysis, none provided a meaningful contribution to a model predicting the detection of prostate cancer based solely on tPSA. The odds ratio for a 1-ng/mL increase in tPSA was 3.69 (95% CI, 2.99-4.56), and tPSA remained a significant predictor even when outlier PSA values ( 4 ng/mL) and young patients ( 44 years) were excluded from the analysis. Total PSA was predictive of prostate cancer even when nonpalpable tumors and tumors diagnosed within 20 years of venipuncture were excluded. Bayesian analysis determined that a tPSA level of 0.5 ng/mL at age 40 could be used to stratify patients according to their risk of developing clinically significant cancer within their lifetimes (ie, cancer diagnosed by age 75). The results of this study have important implications. This study confirms previously published work indicating that patients can be risk-stratified in their 40s—earlier than current recommendations for PSA testing suggest. Although Lilja and colleagues demonstrate nicely that early measurement of PSA correlates with clinically significant cancer, their work does not come without caveats. Prostate-cancer detection does not equate with prostatecancer curability. Are the patients stratified into high-risk groups curable? Otherwise stated, does delaying PSA screening until patients reach their 50s have any effect on outcomes? Also, interestingly, this study establishes that not only tPSA but also fPSA, cPSA, and hK2 are associated with diagnosis of prostate cancer. VOL. 9 NO. 2 2007 REVIEWS IN UROLOGY 91 RIU0338_05-15.qxd 5/15/07 1:49 PM Page 92 Prostate Cancer continued Detection of Life-Threatening Prostate Cancer With Prostate-Specific Antigen Velocity During a Window of Curability Carter HB, Ferrucci L, Kettermann A, et al. J Natl Cancer Inst. 2006;98:1521-1527 This article, published by Carter and colleagues from Johns Hopkins, expands on the theme of early PSA testing by examining the predictive capability of PSA velocity calculated many years prior to diagnosis of prostate cancer. The group bases its study on 2 previous observations: (1) that absolute PSA measured in a man in his 40s is predictive of future prostate-cancer diagnosis, and (2) that absolute PSA levels have a low specificity for the detection of aggressive prostate cancer. Carter and colleagues hypothesize that using a PSA velocity determined from banked serum from the Baltimore Longitudinal Study of Aging (BLSA) may be a better indicator of the presence of life-threatening disease during a window of curability. The group determined PSA velocity in the 10 to 15 years prior to the diagnosis of cancer from a total of 980 men followed in the BLSA—20 of whom died of prostate cancer, 104 of whom either were living with prostate cancer or died with prostate cancer but from another cause, and 856 without prostate cancer. The time frame of 10 to 15 years was chosen because screening is thought to detect prostate cancer with a 10-year lead time, but analyses were also performed for PSA velocities calculated closer to the time of cancer diagnosis. Absolute PSA was correlated with PSA velocity. Velocity was chosen because absolute PSA was not a statistically significant predictor of prostatecancer mortality in a multivariable model. ROC curve analysis suggested that a PSA velocity of 0.35 ng/mL/y was a good cutoff, balancing sensitivity and specificity of life-threatening cancer. Survival of men with PSA velocity  0.35 ng/mL per year (measured 10-15 years prior to diagnosis) was 92% (95% CI, 84%-96%), but only 54% (95% CI, 15%-82%) among men with PSA velocity  0.35 ng/mL per year (P  .001). A Cox proportional hazards model determined that men with PSA velocity  0.35 ng/mL per year had a higher relative risk (RR) of prostate-cancer death than those with PSA velocity 92 VOL. 9 NO. 2 2007 REVIEWS IN UROLOGY  0.35 ng/mL per year (RR 4.7; 95% CI, 1.3-16.5; P
.02). Per 100,000 person-years, men with PSA velocity  0.35 ng/mL per year had a rate of 1240 and men with PSA velocity  0.35 ng/mL per year had a rate of 140. Like the previous study by Lilja and colleagues, this study also recommends obtaining a PSA level from a man in his 40s. In contrast to the previous study, Carter and colleagues recommend using this value to calculate a PSA velocity. This velocity can be used to risk-stratify patients into groups likely never to develop cancer, likely to develop cancer but die of other causes (clinically insignificant cancer), and likely to die of prostate cancer. These data are powerful and can help define groups needing closer or more relaxed surveillance. While studies are ongoing to determine whether PSA screening improves mortality from prostate cancer,6,7 published data continue to demonstrate the utility of PSA in the risk stratification of patients. Further study is necessary before broad-reaching recommendations can be made to implement the screening guidelines similar to the NCCN’s for PSA testing of all men in their 40s. In addition to testing African American men and men with positive family histories of prostate cancer, however, it seems reasonable to offer PSA testing to men who are highly motivated to detect and treat their own prostate cancer. References 1. 2. 3. 4. 5. 6. 7. Smith RA, Cokkinides V, von Eschenbach AC, et al. American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin. 2002;52:8. American Urological Association (AUA). Prostate-specific antigen (PSA) best practice policy. Oncology (Williston Park). 2000;14:267-272, 277-278. National Comprehensive Cancer Network. Prostate cancer early detection. NCCN Clinical Practice Guidelines in Oncology. 2006;6. Available at http://www.nccn.org/professionals/physician_gls/PDF/prostate_detection.pdf. Accessed April 6, 2007. Fang J, Metter EJ, Landis P, et al. Low levels of prostate-specific antigen predict long-term risk of prostate cancer: results from the Baltimore Longitudinal Study of Aging. Urology. 2001;58:411-416. Antenor JA, Han M, Roehl KA, et al. Relationship between initial prostate specific antigen level and subsequent prostate cancer detection in a longitudinal screening study. J Urol. 2004;172:90-93. Schroder FH, Denis LJ, Kirkels W, et al. European randomized study of screening for prostate cancer: progress report of Antwerp and Rotterdam pilot studies. Cancer. 1995;76:129-134. 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(suppl 6):273S-309S.