Screening and Prostate-Cancer Mortality in a Randomized European Study

Transcription

1 Urological Survey Urological Oncology: Prostate Cancer Screening and Prostate-Cancer Mortality in a Randomized European Study F. H. Schröder, J. Hugosson, M. J. Roobol, T. L. Tammela, S. Ciatto, V. Nelen, M. Kwiatkowski, M. Lujan, H. Lilja, M. Zappa, L. J. Denis, F. Recker, A. Berenguer, L. Maattanen, C. H. Bangma, G. Aus, A. Villers, X. Rebillard, T. van der Kwast, B. G. Blijenberg, S. M. Moss, H. J. de Koning and A. Auvinen; ERSPC Investigators N Engl J Med 2009; Epub ahead of print. Background: The European Randomized Study of Screening for Prostate Cancer was initiated in the early 1990s to evaluate the effect of screening with prostate-specific-antigen (PSA) testing on death rates from prostate cancer. Methods: We identified 182,000 men between the ages of 50 and 74 years through registries in seven European countries for inclusion in our study. The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. The predefined core age group for this study included 162,243 men between the ages of 55 and 69 years. The primary outcome was the rate of death from prostate cancer. Mortality follow-up was identical for the two study groups and ended on December 31, Results: In the screening group, 82% of men accepted at least one offer of screening. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The rate ratio for death from prostate cancer in the screening group, as compared with the control group, was 0.80 (95% confidence interval [CI], 0.65 to 0.98; adjusted P 0.04). The absolute risk difference was 0.71 death per 1000 men. This means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. The analysis of men who were actually screened during the first round (excluding subjects with noncompliance) provided a rate ratio for death from prostate cancer of 0.73 (95% CI, 0.56 to 0.90). Conclusions: PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis. Editorial Comment: This landmark study demonstrates unequivocally that PSA screening saves lives. In a monumental undertaking carried out in 7 European countries 162,000 men ages 55 to 69 years were randomized to screening every 4 years using a PSA cutoff of 3 ng/ml versus no screening. With a followup to 14 years the group undergoing screening experienced a 71% increase in the incidence of prostate cancer, a 41% reduction in advanced disease (positive bone scan or PSA greater than 100 ng/ml) and a 20% decrease in deaths from prostate cancer. If one includes only men who actually underwent screening, the decrease in prostate cancer deaths was 27%. As the results of this study mature, it is likely that the mortality benefit will increase further. This finding is similar to the 30% reduction in mortality from breast cancer following screening with mammography, 1 and the 33% reduction in prostate cancer specific mortality that occurred in the United States in 1994 to 2003 following the introduction of PSA screening. However, as the authors point out, to prevent 1 prostate cancer death at 10 years, 1,410 men would need to be screened and 48 additional men would need to be treated. Although the number needed to be screened is similar to mammography in breast cancer and fecal occult blood testing for colorectal cancer, this study came under harsh criticism because of the side effects associated with the treatment of prostate cancer, which in many men might be unnecessary. For this reason if screening for prostate cancer is going to receive popular support, we as urologists need to do 2 things: 1) avoid overdiagnosis in men who are unlikely to have a survival benefit (too old or too ill to live longer than 10 years) and overtreatment in /09/ /0 Vol. 182, , July 2009 THE JOURNAL OF UROLOGY Printed in U.S.A. Copyright 2009 by AMERICAN UROLOGICAL ASSOCIATION DOI: /j.juro

2 146 PROSTATE CANCER men over 65 years with low volume disease, and 2) strive to improve the quality of treatments to reduce their morbidity. 1. Shapiro S, Venet W, Strax P, Venet L and Roeser R: Selection, follow-up, and analysis in the Health Insurance Plan Study: a randomized trial with breast cancer screening. Natl Cancer Inst Monogr 1985; 67: 65. Mortality Results From a Randomized Prostate-Cancer Screening Trial G. L. Andriole, R. L. Grubb, III, S. S. Buys, D. Chia, T. R. Church, M. N. Fouad, E. P. Gelmann, P. A. Kvale, D. J. Reding, J. L. Weissfeld, L. A. Yokochi, E. D. Crawford, P. O Brien, J. D. Clapp, J. M. Rathmell, T. L. Riley, R. B. Hayes, B. S. Kramer, G. Izmirlian, A. B. Miller, P. F. Pinsky, P. C. Prorok, J. K. Gohagan and C. D. Berg; PLCO Project Team N Engl J Med 2009; 360: Background: The effect of screening with prostate-specific-antigen (PSA) testing and digital rectal examination on the rate of death from prostate cancer is unknown. This is the first report from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial on prostate-cancer mortality. Methods: From 1993 through 2001, we randomly assigned 76,693 men at 10 U.S. study centers to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the screening group were offered annual PSA testing for 6 years and digital rectal examination for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended. The numbers of all cancers and deaths and causes of death were ascertained. Results: In the screening group, rates of compliance were 85% for PSA testing and 86% for digital rectal examination. Rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41 to 46% for digital rectal examination. After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the control group (rate ratio, 1.22; 95% confidence interval [CI], 1.16 to 1.29). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The data at 10 years were 67% complete and consistent with these overall findings. Conclusions: After 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups. Editorial Comment: Does not everyone already agree that PSA screening and aggressive treatment do more harm than good in men with a lifespan of less than 10 years? Then why did this article dominate the news when it was released online in the same issue of New England Journal of Medicine as the landmark paper by Schröder et al (see preceding comment)? Conveniently the words less than 10 years were left out of the sound bites. But this is only one of many problems with this trial. To set the record straight, urologists, their patients and their referring physicians need to fully understand its many shortcomings. This report from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) analyzes 77,000 men (half the size of the European trial) who were randomized to no screening versus PSA screening for 6 years using a cut-point of 4.0 ng/ml and digital rectal examination for 4 years. At 7 years the authors report no improvement in prostate cancer specific survival. However, this should come as no surprise because in the positive trial by Schröder et al there was also no significant improvement seen at 7 years. However, the problems just begin there. This trial also failed to achieve some of the important milestones that are characteristic of screening trials. To reduce mortality, screening should significantly increase the number of new cases and improve clinical stage. 1 For example in the trial by Schroeder et al screening resulted in a 71% increase in the incidence of prostate cancer and a 41% reduction in advanced disease (positive bone scan or PSA greater than 100 ng/ml). In contrast, screening in the PLCO trial increased the incidence by only 17% at 10 years and resulted in no improvement in clinical stage. For this reason with longer followup there is no reason to believe that the impact on mortality will change.

3 PROSTATE CANCER 147 What is wrong with this study? First, it did not compare screening to no screening; rather it compared less screening to more screening. In the screening arm 85% of patients underwent PSA testing compared to 52% of the controls. That is right, only a 33% difference. Furthermore, at baseline 44% of the patients in the screened and control groups already had 1 or more PSA tests. Yes, 44% of the men had already been screened before entering the trial and, therefore, were at lower risk for having prostate cancer. This explains why there were only a very small number of deaths from prostate cancer in either arm; men with life threatening disease were identified earlier and were excluded from this analysis. Finally the methods of diagnosis were outdated and flawed: 1) the PSA cutoff of 4.0 ng/ml is outdated and PSA velocity, which has been shown to predict mortality from prostate cancer in men with PSA levels lower than 4 ng/ml, 2 was not used; and 2) only 30% of the screened men who developed an elevated PSA actually underwent a biopsy! 3 This may have contributed to increased deaths from prostate cancer in the screened group. It is unfortunate that these shortcomings were not included in the widespread coverage this article received in the press. For this reason we need to emphasize these flaws when we counsel our patients: 1) the absence of a mortality benefit at 7 years is meaningless; 2) the study did not evaluate screening versus no screening, but instead looked at more screening (85%) versus less (52%); 3) the PSA cutoff was 4.0 ng/ml, not 2.5 ng/ml, and PSA velocity was not used; 4) of screened men who developed an elevated PSA only 30% underwent a biopsy; and 5) almost half of the men in this study were at lower risk for cancer because they had undergone PSA testing before entering the trial. Because this study was poorly planned and executed, the results of this trial are worthless when giving advice to a healthy man about impact on death from prostate cancer if he undergoes intelligent screening with PSA, a prompt biopsy when an abnormality is found and effective therapy. 1. Kvale R, Auvinen A, Adami HO, Klint A, Hernes E, Moller B et al: Interpreting trends in prostate cancer incidence and mortality in the five Nordic countries. J Natl Cancer Inst 2007; 99: Carter HB, Ferrucci L, Kettermann A, Landis P, Wright EJ, Epstein JI et al: Detection of life-threatening prostate cancer with prostate-specific antigen velocity during a window of curability. J Natl Cancer Inst 2006; 98: Grubb RL III, Pinsky PF, Greenlee RT, Izmirlian G, Miller AB, Hickey TP et al: Prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial: update on findings from the initial four rounds of screening in a randomized trial. BJU Int 2008; 102: Use of 5- -Reductase Inhibitors for Prostate Cancer Chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline B. S. Kramer, K. L. Hagerty, S. Justman, M. R. Somerfield, P. C. Albertsen, W. J. Blot, H. B. Carter, J. P. Costantino, J. I. Epstein, P. A. Godley, R. P. Harris, T. J. Wilt, J. Wittes, R. Zon and P. Schellhammer National Institutes of Health, Bethesda, International Epidemiology Institute, Rockville and Johns Hopkins University, Baltimore, Maryland; American Society of Clinical Oncology, Alexandria and Eastern Virginia Medical School, Norfolk, Virginia; University of Montana Liberal Studies, Missoula, Montana; University of Connecticut Health Center, Farmington, Connecticut; National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, Pennsylvania; University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; University of Minnesota School of Medicine, Minneapolis, Minnesota; Statistics Collaborative, Washington, D.C.; and Michiana Hematology Oncology, Granger, Indiana J Clin Oncol 2009; 27: Purpose: To develop an evidence-based guideline on the use of 5-alpha-reductase inhibitors (5-ARIs) for prostate cancer chemoprevention. Methods: The American Society of Clinical Oncology (ASCO) Health Services Committee (HSC), ASCO Cancer Prevention Committee, and the American Urological Association Practice Guidelines Committee jointly convened a Panel of experts, who used the results from a systematic review of the literature to develop evidence-based recommendations on the use of 5-ARIs for prostate cancer chemoprevention. Results: The systematic review completed for this guideline identified 15 randomized clinical trials that met the inclusion criteria, nine of which reported prostate cancer period prevalence. Conclusion: Asymptomatic men with a prostate-specific antigen (PSA) 3.0 ng/ml who are regularly screened with PSA or are anticipating undergoing

4 148 PROSTATE CANCER annual PSA screening for early detection of prostate cancer may benefit from a discussion of both the benefits of 5-ARIs for 7 years for the prevention of prostate cancer and the potential risks (including the possibility of high-grade prostate cancer). Men who are taking 5-ARIs for benign conditions such as lower urinary tract [obstructive] symptoms (LUTS) may benefit from a similar discussion, understanding that the improvement of LUTS relief should be weighed with the potential risks of highgrade prostate cancer from 5-ARIs (although the majority of the Panel members judged the latter risk to be unlikely). A reduction of approximately 50% in PSA by 12 months is expected in men taking a 5-ARI; however, because these changes in PSA may vary across men, and within individual men over time, the Panel cannot recommend a specific cut point to trigger a biopsy for men taking a 5-ARI. No specific cut point or change in PSA has been prospectively validated in men taking a 5-ARI. Editorial Comment: Just after reading this article in Journal of Clinical Oncology I heard a malpractice advertisement on television that rang a bell. It made me worry that well-meaning oncologists who follow the advice in this guideline may be vulnerable because of what the article does not say. For this reason, unfortunately, some day we may hear another advertisement that goes like this: Do you have aggressive prostate cancer even though your doctor placed you on a pill he said would prevent the disease? Did you know that it was not approved by the Food and Drug Administration (FDA) for this purpose, that it does not prevent the disease, but only lowers your PSA, lulling you into a false sense of security, and that there were ways that your PSA could have been monitored to detect your cancer earlier? Unfortunately all of these statements are true because the guideline omits 3 important considerations that should influence a decision about whether patients should receive 5 -reductase inhibitors for chemoprevention. 1) The drug is not FDA approved for this purpose. 2) The 25% reduction in cancer in the Prostate Cancer Prevention Trial occurred largely because 15% fewer men underwent a biopsy. In the men who actually underwent a biopsy because of an elevated PSA or abnormal digital rectal examination finasteride reduced the risk of a positive biopsy by only 10% (the biopsy was positive in 26.5% of men on finasteride and in 29% of men on placebo, a 10% difference that is not statistically significant). 1 Thus, finasteride has no primary effect on preventing prostate cancer. 3) In men on finasteride if the PSA ever begins to rise, a biopsy should be considered because their risk of having cancer is 3-fold higher than in men without a rise in PSA and 6-fold higher for being diagnosed with high grade disease. 2 What will the oncologists have as their defense? There is 1 simple statement: 5 - Reductase inhibitors do not eliminate the risk of developing cancer; they reduce its clinical incidence. This distinction should be made clear. That statement stands alone without any of the above backup information provided. What patient or physician is going to be able to figure out the difference between developing cancer and clinical incidence? If you come across a patient who wants to be treated with finasteride for chemoprevention, and wish to make certain that he has been fully informed about the pros and cons, you should look at the informed consent that I formulated. 3 And there may be a lot of men who will use it. I am told that based on the publicity surrounding the release of this guideline, many young men look on the use of Propecia (finasteride) as a no-brainer prevent baldness and prostate cancer with 1 pill a day. 1. Wilt TJ, MacDonald R, Hagerty K, Schellhammer P and Kramer BS: 5- -reductase inhibitors for prostate cancer prevention. Cochrane Database Syst Rev 2008; 2: CD Thompson IM, Pauler Ankerst D, Chi C, Goodman PJ, Tangen CM, Lippman SM et al: Prediction of prostate cancer for patients receiving finasteride: results from the Prostate Cancer Prevention Trial. J Clin Oncol 2007; 25: Walsh PC. Reply to letter. AUA News. Available at

5 PROSTATE CANCER 149 Vitamin and Mineral Use and Risk of Prostate Cancer: The Case-Control Surveillance Study Y. Zhang, P. Coogan, J. R. Palmer, B. L. Strom and L. Rosenberg Clinical Epidemiology Research and Training Unit, School of Medicine, Boston University, Boston, Massachusetts Cancer Causes Control 2008; Epub ahead of print. Background: Many studies have evaluated the association between vitamin and mineral supplement use and the risk of prostate cancer, with inconclusive results. Methods: The authors examined the relation of use of multivitamins as well as several single vitamin and mineral supplements to the risk of prostate cancer risk among 1,706 prostate cancer cases and 2,404 matched controls using data from the hospital-based case-control surveillance study conducted in the United States. Odds ratios (OR) and 95% confidence intervals (CI) for risk of prostate cancer were estimated using conditional logistic regression model. Results: For use of multivitamins that did not contain zinc, the multivariable odds ratios of prostate cancer were 0.6 for 1 4 years, 0.8 for 5 9 years, and 1.2 for 10 years or more, respectively (p for trend 0.70). Men who used zinc for ten years or more, either in a multivitamin or as a supplement, had an approximately two-fold (OR 1.9, 95% CI: 1.0, 3.6) increased risk of prostate cancer. Vitamin E, beta-carotene, folate, and selenium use were not significantly associated with increased risk of prostate cancer. Conclusion: The finding that long-term zinc intake from multivitamins or single supplements was associated with a doubling in risk of prostate cancer adds to the growing evidence for an unfavorable effect of zinc on prostate cancer carcinogenesis. Editorial Comment: Evidence against the value of multivitamins as a preventive strategy for cancer and cardiovascular disease is mounting. This study once again shows that multivitamins do not prevent prostate cancer, and that men who take zinc for 10 years either in multivitamins or as supplements have a 2-fold increased risk for developing the disease. After reading this article I threw away the multivitamin that I was taking that was specially formulated for adults of 50. Other Malignancies in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma A. M. Tsimberidou, S. Wen, P. McLaughlin, S. O Brien, W. G. Wierda, S. Lerner, S. Strom, E. J. Freireich, L. J. Medeiros, H. M. Kantarjian and M. J. Keating Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, Texas J Clin Oncol 2009; 27: Purpose: Other malignancies have been reported to occur with increased frequency in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The aim of this study was to determine the frequency, outcomes, and factors associated with other cancers in patients with CLL/SLL. Patients and Methods: We reviewed the records of consecutive patients with previously untreated CLL/SLL seen at The University of Texas M. D. Anderson Cancer Center from 1985 to The number of second cancers observed was compared with the number expected from the Surveillance, Epidemiology, and End Results database. Results: Among 2,028 patients, 324 (16%) had a history of other cancers and 227 (11.2%) developed other malignancies during the follow-up period. Overall, 625 cancers were observed in 551 patients, including skin (30%), prostate (13%), breast (9%), melanoma (8%), lymphoma (8%), gastrointestinal (9%), lung (6%), and other cancers (17%). The risk of a second cancer was 2.2 times higher than the expected risk. The response rates in patients with and without a history of other cancers were 86% and 92%, respectively (P.04), and the 5-year survival rates were 70% and 82%, respectively (P.001). In Cox analysis, independent factors predicting development of new cancers were older age, male sex, and elevated levels of beta2-microglobulin, lactate dehydrogenase, and creatinine. In patients who were treated for CLL/SLL, the treatment regimen did not affect

6 150 GERIATRICS the risk of subsequent cancer (P.49). Conclusion: Patients with CLL/SLL have more than twice the risk of developing a second cancer and an increased frequency of certain cancer types. Awareness of risk factors could permit early detection. Editorial Comment: In my experience it is not unusual to diagnose chronic lymphocytic leukemia in men undergoing a pelvic lymphadenectomy for prostate cancer. This study shows that about a third of men with chronic lymphocytic leukemia develop another cancer, of which 13% arise in the prostate. Incidence and Mortality of Incidental Prostate Cancer: A Swedish Register-Based Study O. Andren, H. Garmo, L. Mucci, S. O. Andersson, J. E. Johansson and K. Fall Department of Urology, Orebro University Hospital, Orebro, Sweden Br J Cancer 2009; 100: In a national register-based study of incidence trends and mortality of incidental prostate cancer in Sweden, we found that a significant proportion (26.6%) of affected men diagnosed died of their disease, which challenges earlier descriptions of incidental prostate cancer as a non-lethal disease. Editorial Comment: For years, based on studies from Sweden, it was widely stated that men with prostate cancer rarely die of the disease. However, with longer followup it has become very clear that in men with incidentally diagnosed prostate cancer detected by transurethral resection of the prostate by 10 years approximately a third died of prostate cancer. Beginning in 1993, however, cancer specific mortality improved. Geriatrics Radical Prostatectomy in Men Aged >70 Years: Effect of Age on Upgrading, Upstaging, and the Accuracy of a Preoperative Nomogram L. Richstone, F. J. Bianco, H. H. Shah, M. W. Kattan, J. A. Eastham, P. T. Scardino and D. S. Scherr Smith Institute for Urology, North Shore LIJ Health System, New York, New York BJU Int 2008; 101: Objectives: To determine the effect of age on clinicopathological features, the accuracy of the preoperative nomogram, and survival after radical retropubic prostatectomy (RRP), as there are limited data on elderly men undergoing RRP. Patients and Methods: A database of 258 men aged 70 years and 3777 aged 70 years who had RRP was reviewed to compare the clinicopathological features and survival between the age groups. The effect of age on the frequency of upgrading from biopsy Gleason sum 2-6 to pathology Gleason sum 7, and upstaging from clinical T1-T2 to pathological stage T3-T4 was also evaluated. Results: Men aged 70 years had cancers of higher clinical stage (P 0.001), pathology Gleason sums (P 0.01) and a lower frequency of organ-confined disease than men aged 70 years (58.1% and 69.9%, respectively, P 0.001). There was upgrading in 76/169 (45.0%) men aged 70 years and in 936/2656 (35.2%) of men aged 70 years (P 0.01). However, age was not associated with upgrading on a multivariate analysis. Upstaging was more frequent in older than in younger men (40.2% and 29.3%, respectively, P 0.001). Age 70 years was associated with upstaging on multivariate logistic regression but did not affect the accuracy of the Partin tables (P 0.14) or Kattan nomograms (P 0.53). There was no difference in cancer-specific survival (96% at 10 years, P 0.33) or biochemical progression-free probability between the age groups (74% and