Prostate Cancer

News and Views From the Literature

9a. RIU0443_10-22.qxd 10/22/09 4:30 PM Page 179 Female Urology: Training and Regulations lower exposure rates in the range of 1% to 3% for slings, but with the larger area of mesh used in prolapse repairs, the rate increases to up to 10%. With the current widespread use of graft materials to reinforce pelvic floor reconstructive techniques, it is imperative for surgeons to be familiar with potential complications related to the materials and proper management of these complications. Although it appears that the benefit of using some synthetic materials may outweigh the risks, proper management and understanding of the risks is important to counsel our patients appropriately and responsibly prior to surgery. Prostate Cancer Randomized Trials of Prostate Cancer Screening Reviewed by Stacy Loeb, MD, Alan W. Partin, MD, PhD The James Buchanan Brady Urological Institute, Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD [Rev Urol. 2009;11(3):179-180 doi: 10.3909/riu0463] © 2009 MedReviews®, LLC ince the introduction of widespread prostate-specific antigen (PSA)–based prostate cancer screening, there has been a considerable stage migration.1 Prior studies have shown that PSA screening reduces the risk of advanced disease compared with no screening,2,3 but there were insufficient data to prove that screening saves lives. Until recently, randomized trials demonstrating Level I evidence have not been available to determine whether prostate cancer screening leads to a mortality benefit. In March 2009, the European Randomized Study of Screening for Prostate Cancer (ERSPC) and Prostate, Lung, Colorectal, and Ovarian (PLCO) trials reported on mortality results. S Screening and Prostate-Cancer Mortality in a Randomized European Study Schröder FH, Hugosson J, Roobol MJ, et al. N Engl J Med. 2009;360:1320-1328. Schröder and colleagues reported on the mortality rates in 162,243 men aged 55 to 69 years from ERSPC. Men from 7 European countries were identified through population registries and randomized into screening and control arms. It is noteworthy that PSA screening was uncommon in Europe at the time this trial was initiated, such that this represented a population with relatively low levels of prescreening. Most centers performed screening at 4-year intervals and used a serum PSA level of 3 ng/mL as the threshold for biopsy, although digital rectal examination (DRE) was primarily used as an ancillary test for men with PSA levels greater than 3 ng/mL. The mean age was 60.8 years at randomization and men in the screening arm received an average of 2.1 PSA tests per person. The cumulative incidence of prostate cancer was 8.2% in the screening arm and 4.8% in the control arm. Thus, screening compared with no screening led to an expected increase in prostate cancer incidence. At a median follow-up of approximately 9 years, prostate cancer death occurred in 214 men from the screening arm versus 326 controls (adjusted rate ratio 0.80; 95% confidence interval [CI], 0.65-0.98; P  .04) in the intent-to-screen analysis. A separate analysis of men who actually underwent screening in the first round (82% compliance) to those who did not demonstrated a 27% reduction in prostate cancer mortality. Of note, the difference in mortality emerged after 7 to 8 years, and appeared to increase over time. In addition to the reduction in mortality, the screening arm had a 41% lower rate of metastases at the time of diagnosis than the control arm. Despite the favorable mortality results, Schröder and colleagues also highlighted the potential harms of screening with respect to overdiagnosis. The prostate cancer incidence rate was 70% higher in the screening arm than the control arm. As a comparison, a systematic review of breast cancer screening similarly demonstrated a 15% to 20% relative reduction in cancer-specific mortality with mammography, with only a 30% increase in incidence.4 Overall, Schröder and colleagues estimated that 1410 men would need to be screened and an additional 48 men treated to prevent 1 prostate cancer death over 9 years. However, the number needed to treat to prevent 1 case of metastatic prostate cancer was approximately 25 compared with the ERSPC control group (F. H. Schröder, MD, personal communication, 2009), and only 15 compared with a population from Northern Ireland with virtually no screening.5 Mortality Results From a Randomized Prostate-Cancer Screening Trial Andriole GL, Crawford ED, Grubb RL 3rd, et al. N Engl J Med. 2009;360:1310-1319. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial was designed by the National Cancer VOL. 11 NO. 3 2009 REVIEWS IN UROLOGY 179 9a. RIU0443_10-22.qxd 10/22/09 4:30 PM Page 180 Prostate Cancer continued Institute to determine whether screening with PSA and DRE, flexible sigmoidoscopy, chest x-ray, and CA-125 with transvaginal ultrasound would reduce mortality from prostate, colorectal, lung, and ovarian cancer, respectively.6 Beginning in 1993, the prostate cancer portion of the trial randomized 76,693 men aged 55 to 74 years to screening or “usual care.” The screening protocol included annual DRE for 4 years and annual PSA testing for 6 years. Although participants were notified of abnormal test results (defined as a suspicious DRE or PSA > 4 ng/mL), the subsequent diagnostic workup and/or treatment was not mandated by the study protocol. As a result, a proportion of screened men who developed an abnormal PSA or DRE did not undergo prompt prostate biopsy,7 conditions that were designed to approximate a real-world setting. This updated report from Andriole and associates found no difference in prostate cancer mortality between men randomized to screening or no screening at 7 years (rate ratio 1.13; 95% CI, 0.75-1.70). Interestingly, prostate cancer incidence differed by only 17% between the screening and control arms at 10 years. A possible explanation underlying these findings is that 44% of participants had at least 1 PSA test within 3 years of study entry, and 52% of controls were screened (“contamination”) during the study period. Because these numbers were based upon self-report, it is possible that they represent underestimates8 in light of the high prevalence of opportunistic PSA testing in the United States.9 Several differences between the ERSPC and PLCO studies should be highlighted, including the sample size (162,243 vs 76,693), screening intervals (every 4 years vs annual), PSA threshold for biopsy (3 ng/mL vs 4 ng/mL), and use of DRE (ancillary test vs annual for 4 years). Also, the rates of prescreening and contamination were both considerably lower in the ERSPC, and the median follow-up for prostate cancer mortality was longer (9 years vs 5-6 years). Many of these methodological differences may help to explain the disparate results 180 VOL. 11 NO. 3 2009 REVIEWS IN UROLOGY between the studies. Nevertheless, the conflicting results of these trials and concerns over the benefit-to-harm ratio led Michael Barry to conclude in an accompanying editorial that PSA screening is the “controversy that refuses to die.”10 Overall, the authors conclude based upon the ERSPC results that screening does lead to a reduction in prostate cancer mortality. Furthermore, the potential harms of screening might be reduced through more careful patient selection for both screening and treatment. In addition, the future discovery of better biomarkers for clinically significant prostate cancer and an ongoing reduction in treatment-related morbidity could further shift the risk-tobenefit ratio in favor of screening. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA. 1993;270:948-954. Aus G, Bergdahl S, Lodding P, et al. Prostate cancer screening decreases the absolute risk of being diagnosed with advanced prostate cancer—results from a prospective, population-based randomized controlled trial. Eur Urol. 2007;51:659-664. van der Cruijsen-Koeter IW, Roobol MJ, Wildhagen MF, et al. Tumor characteristics and prognostic factors in two subsequent screening rounds with fouryear interval within prostate cancer screening trial, ERSPC Rotterdam. Urology. 2006;68:615-620. Gøtzsche PC, Nielsen M. Screening for breast cancer with mammography. Cochrane Database Syst Rev. 2006;(4):CD001877. van Leeuwen PJ, Connolly D, Napolitano G, et al. Metastasis-free survival in screen and clinical detected prostate cancer: a comparison between the European Randomized Study of Screening for Prostate Cancer and Northern Ireland. J Urol. 2009;181:798. Abstract 2203. 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(6 suppl):273S-309S. Pinsky PF, Andriole GL, Kramer BS, et al. Prostate biopsy following a positive screen in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. J Urol. 2005;173:746-750; discussion 750-751. Chan EC, Vernon SW, Ahn C, Greisinger A. Do men know that they have had a prostate-specific antigen test? Accuracy of self-reports of testing at 2 sites. Am J Public Health. 2004;94:1336-1338. Sirovich BE, Schwartz LM, Woloshin S. Screening men for prostate and colorectal cancer in the United States: does practice reflect the evidence? JAMA. 2003;289:1414-1420. Barry MJ. Screening for prostate cancer—the controversy that refuses to die. N Engl J Med. 2009;360:1351-1354.