News and Views From the Literature

Prostate Cancer

Literature review News and Views From the Literature Prostate Cancer Update of Randomized Trials for Prostate Cancer Screening Annelies Vellekoop, MD, Stacy Loeb, MD From the Department of Urology, New York University, New York, NY [ Rev Urol. 2013;15(1):37-39 doi: 10.3909/riu0570] © 2013 MedReviews®, LLC P rostate cancer screening remains controversial despite the publication of results from several randomized trials. The two most important trials are the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial. Results from both trials were published simultaneously in 2009.1 At that time, the ERSPC reported a 20% reduction in prostate cancer-specific mortality with screening (relative risk [RR] 0.80; 95% confidence interval [CI], 0.65-0.98; P 5 .04),2 whereas the PLCO trial found no significant mortality difference between the screening and control arms.3 Updated results from both trials with additional follow-up were recently published,4,5 which are reviewed here. Prostate Cancer Mortality at 11 Years of Follow-up Schröder FH, Hugosson J, Roobol M, et al. N Engl J Med. 2012;366:981-990. The aim of this study was to present an update of the prostate cancer mortality in the ERSPC, which included 182,160 men, aged 50 to 74 years, from eight European countries, with a core age group of 162,388 men aged 55 to 69 years. The trial protocol has been described previously.2 The primary endpoint was prostate cancer mortality. Overall, 136,689 screening tests were performed in the core age group and 16.6% were positive. Compliance with a recommended biopsy was 85.9%. Prostate cancer was diagnosed in 6963 men in the screening arm (cumulative incidence 5 9.6%) and 5396 (cumulative incidence 5 6.0%) in the control arm. Thus, screening compared with no screening led to an expected increase in prostate cancer incidence (RR 1.63; 95% CI, 1.57-1.69), or a difference of 3.71 cases per 1000 person-years. Most of the excess cases in the screening group were lowerrisk tumors, and screening was associated with a significant reduction in advanced/metastatic disease.6 During follow-up, prostate cancer-specific death occurred in 299 men in the screening arm and 462 controls, or a RR reduction of 21% in favor of screening (RR 0.79; 95% CI, 0.68-0.91) in the intent-to-treat analysis. Vol. 15 No. 1 • 2013 • Reviews in Urology • 37 4004170006_RIU0570.indd 37 08/04/13 2:06 PM Prostate Cancer continued A secondary analysis correcting for noncompliance and selection bias found an even greater prostate cancer mortality reduction of 29%. In addition, during 10- and 11-year follow-up, a greater RR reduction of 38% was reported. Despite the reduction in prostate cancer mortality, screening had no effect on all-cause mortality (RR 0.99; 95% CI, 0.97-1.01). This is not surprising given that the study was not powered to address overall survival (OS). In contrast to treatment trials, the primary endpoint of the ERSPC and other screening trials is cancer-specific mortality.7 Finally, the investigators calculated the number of men that needed to be invited (NNI) to screening and the number needed to be diagnosed (NND) with prostate cancer (but not necessarily treated) to prevent a disease-specific death. In 2009, the authors reported that 1410 men had to be screened and 48 treated to prevent 1 prostate cancer death. Because the prostate cancer mortality curves had only recently started to separate at that time, modeling studies projected that these numbers would improve over time.8 Indeed, at 11-year follow-up, the ERSPC reported an NNI of 1055 and NND of 37. Using all available follow-up, the NNI and NND were 936 and 33, respectively. Overall, this is the largest trial providing Level 1 evidence that prostate-specific antigen (PSA) screening reduces metastasis and death from prostate cancer, with an increase in the observed benefit since the last interim analysis. Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: Mortality Results After 13 Years of Follow-up Andriole GL, Crawford ED, Grubb RL 3rd, et al. Natl Cancer Inst. 2012;104:125-132. The PLCO trial included a total of 76,685 men, aged 55 to 74 years, who were screened at 10 centers between 1993 and 2001, with follow-up assessed through December 2009. The intervention group (38,340 men) had annual PSA testing for 6 years and a digital rectal examination (DRE) for 4 years. A positive test result was defined as a PSA of > 4 ng/mL or a suspicious DRE. The control group (38,345) was randomized to usual care, which most commonly included PSA screening in the United States. Ninety-two percent of men were followed for 10 years and 57% completed 13 years of follow-up. Compared with the ERSPC, there was a relatively modest 12% increase of prostate cancer incidence in the screening arm (RR 1.12; 95% CI, 1.07-1.17), likely due to the widespread opportunistic screening among controls. There was a trend toward less high-grade prostate cancer in the screening arm that did not reach statistical significance (RR 5 0.89; 95% CI, 0.77-1.01). There was also no significant difference in the primary endpoint of prostate cancer mortality between the intervention and control arms (RR 1.09; 95% CI, 0.87-1.36). As in the ERSPC, there was no significant difference in OS, but the study was not powered to address that endpoint. In addition, several subset analyses were reported, including an assessment of the influence of comorbidities on the mortality effect of screening. Previously, the same authors reported a significant survival benefit from screening among men with minimal comorbidity.9 Using a different comorbidity definition, in the current study they reported that there was no statistically significant effect modification of screening benefit by comorbidity. As described, there are numerous differences between the ERSPC and PLCO trials. The ERSPC was approximately twice as large, and the extent of opportunistic PSA screening in the control arms differs. In the PLCO trial, 45% of men had at least one PSA test in the 3 years before randomization, the majority of controls underwent screening during the trial, and many men with abnormal screening results did not receive a prompt biopsy.10 By contrast, in the ERSPC trial, the estimated contamination rate was 15% early in the trial and biopsy compliance was good. Thus, the ERSPC was better able to compare screening with no screening, whereas the PLCO compared organized annual screening with frequent opportunistic screening.11 It is noteworthy that neither study included men in their 40s, and both protocols used the total PSA level to determine the need for biopsy. This is in contrast to contemporary clinical practice, where a risk-adapted multivariable approach is increasingly advocated.12 Because these trials were initiated in the 1990s, screening has progressed substantially, and additional highquality evidence regarding new approaches is ultimately needed. The substantial differences in the design and conduct of these two trials is likely what is responsible for the seemingly divergent results. The best-quality evidence to date suggests that screening increases the diagnosis of low-risk prostate cancer, but also reduces metastatic disease and prostate cancer death. Supported by the Louis Feil Charitable Trust. 38 • Vol. 15 No. 1 • 2013 • Reviews in Urology 4004170006_RIU0570.indd 38 08/04/13 2:06 PM Prostate Cancer References 1. 2. 3. 4. 5. 6. Loeb S, Partin AW. Randomized trials of prostate cancer screening. Rev Urol. 2009;11: 179-180. Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320-1328. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310-1319. Schröder FH, Hugosson J, Roobol MJ, et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med. 2012;366:981-990. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst. 2012;104:125-132. Schröder FH, Hugosson J, Carlsson S, et al. Screening for prostate cancer decreases the risk of developing metastatic disease: findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC). Eur Urol. 2012;62:745-752. 7. 8. 9. 10. 11. 12. Steele RJ, Brewster DH. Should we use total mortality rather than cancer specific mortality to judge cancer screening programmes? No. BMJ. 2011;343:d6397. Loeb S, Vonesh EF, Metter EJ, et al. What is the true number needed to screen and treat to save a life with prostate-specific antigen testing? J Clin Oncol. 2011;29:464-467. Crawford ED, Grubb R 3rd, Black A, et al. Comorbidity and mortality results from a randomized prostate cancer screening trial. J Clin Oncol. 2011;29:355-361. 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. Cooperberg MR, Carroll PR. Prostate-cancer screening. N Engl J Med. 2009;361:203; author reply 204-205. Zhu X, Albertsen PC, Andriole GL, et al. Risk-based prostate cancer screening. Eur Urol. 2012;61:652-661. Vol. 15 No. 1 • 2013 • Reviews in Urology • 39 4004170006_RIU0570.indd 39 08/04/13 2:06 PM