Roger Chou, MD; Jennifer M. Croswell, MD, MPH; Tracy Dana, MLS; Christina Bougatsos, BS; Ian Blazina, MPH; Rongwei Fu, PhD; Ken Gleitsmann, MD, MPH; Helen C. Koenig, MD, MPH; Clarence Lam, MD, MPH; Ashley Maltz, MD, MPH; J. Bruin Rugge, MD, MPH; Kenneth Lin, MD
Screening can detect prostate cancer at earlier, asymptomatic stages, when treatments might be more effective.
To update the 2002 and 2008 U.S. Preventive Services Task Force evidence reviews on screening and treatments for prostate cancer.
MEDLINE (2002 to July 2011) and the Cochrane Library Database (through second quarter of 2011).
Randomized trials of prostate-specific antigen–based screening, randomized trials and cohort studies of prostatectomy or radiation therapy versus watchful waiting, and large observational studies of perioperative harms.
Investigators abstracted and checked study details and quality using predefined criteria.
Of 5 screening trials, the 2 largest and highest-quality studies reported conflicting results. One found that screening was associated with reduced prostate cancer–specific mortality compared with no screening in a subgroup of men aged 55 to 69 years after 9 years (relative risk, 0.80 [95% CI, 0.65 to 0.98]; absolute risk reduction, 0.07 percentage point). The other found no statistically significant effect after 10 years (relative risk, 1.1 [CI, 0.80 to 1.5]). After 3 or 4 screening rounds, 12% to 13% of screened men had false-positive results. Serious infections or urine retention occurred after 0.5% to 1.0% of prostate biopsies. There were 3 randomized trials and 23 cohort studies of treatments. One good-quality trial found that prostatectomy for localized prostate cancer decreased risk for prostate cancer–specific mortality compared with watchful waiting through 13 years of follow-up (relative risk, 0.62 [CI, 0.44 to 0.87]; absolute risk reduction, 6.1%). Benefits seemed to be limited to men younger than 65 years. Treating approximately 3 men with prostatectomy or 7 men with radiation therapy instead of watchful waiting would each result in 1 additional case of erectile dysfunction. Treating approximately 5 men with prostatectomy would result in 1 additional case of urinary incontinence. Prostatectomy was associated with perioperative death (about 0.5%) and cardiovascular events (0.6% to 3%), and radiation therapy was associated with bowel dysfunction.
Only English-language articles were included. Few studies evaluated newer therapies.
Prostate-specific antigen–based screening results in small or no reduction in prostate cancer–specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary.
Agency for Healthcare Research and Quality.
Examining the tradeoffs between potential benefits and harms of prostate cancer screening is a hot topic.
This updated systematic review for the U.S. Preventive Services Task Force found the following: screening based on prostate-specific antigen led to detection of more cases of prostate cancer, small to no reduction in prostate cancer–specific mortality after about 10 years, and several potential harms related to false-positive test results and subsequent evaluations and therapies.
Evidence regarding the mortality-associated benefits of screening conflicted.
The clinical benefits of screening for prostate cancer remain uncertain. Consequences include evaluations and treatments that have associated complications and that may be unnecessary.
BMJ = British Medical Journal; ERSPC = European Randomized Study of Screening for Prostate Cancer; PLCO = Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.
* Not a randomized, controlled trial; systematic review; or meta-analysis; or was a nonrandomized analysis of a randomized, controlled trial.
KQ = key question; RCT = randomized, controlled trial.
* Cochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews.
† Identified from reference lists, suggested by experts, or other methods.
‡ Excluding studies of androgen deprivation therapy, cryotherapy, and high-intensity focused ultrasonography (see the full technical report 8).
Appendix Table 1.
Appendix Table 2.
Appendix Table 3.
Appendix Table 4.
Appendix Table 5.
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Murray S.Feldstein, Urologist
Mayo Clinic Arizona
October 11, 2011
USPSTF needs to consider another endpoint besides mortality
While there is much to applaud in the task force's report, I think their conclusions may do more harm than good. They have studied mortality as a primary endpoint. As an elderly urologist who spent almost half of his career in the pre-PSA era, I can personally attest to another and perhaps even more important factor that is being overlooked: that of suffering from advanced prostate cancer.
No longer do I see patients with bulky cancers who bleed and obstruct their urinary tracts. Many of these patients required emergency procedures and were left with permanent indewelling catheters. The patient presenting with diffuse painful osseous metastasis is now rare. Performing emergency orchiectomies plus radiation or surgical decompression for impending paraplegia seems less common.
Patients like these could live for years and still die of other diseases. They will not register as a success of PSA screening if only mortality is considered. In one study that studied the presence of metastasis as the primary endpoint, screened patients experienced a 48% reduction in the number of patients developing metastatic disease.1
The task force has made some excellent points. The AUA has modified its guidelines to take into account the evidence as it has emerged. More judicious use of PSA and recommendations for treatment of early cancer are necessary. Better methods for distinguishing those cancers destined to spread or kill need to be developed. However, if the task force's conclusions are interpreted by the public at large as a condemnation of early diagnosis of prostate cancer using PSA, we will be thrown back to the era when digital rectal exams diagnosed dangerous cancers too late.
Respectfully, Murray S. Feldstein M.D. Phoenix Arizona
1. Aus G, Bergdahl S, Lodding P., Lilja H, Hugosson J; Prostate cancer screening decreases the absolute risk of being diagnosed with advanced prostate cancer--results from a prospective, population-based randomized controlled trial. Eur J Urol 51: 659-64, 2007
M'Liss A.Hudson, MD
Washington University in St. Louis School of Medicine, Division of Urology
October 19, 2011
Need to Consider Racial Diversity of American Population
To the Editor:
I am disheartened by the publication of "Screening for Prostate Cancer: A Review of the Evidence for the U.S. Preventive Services Task Force" which suggests PSA screening is ineffective and harmful to American men. I do not believe the "exhaustive review of the latest eveidence" dscribed by the authors is applicable to American men.
American Cancer Society Cancer Fact and Figures for African Americans 2011-12 continue to report that 35,110 cases of prostate cancer are expected to occur in AA men, accounting for 40% of all cancer diagnosed in AA men. One in five men will be diagnosed with prostate cancer in their lifetime. The average annual prostate cancer incidence rate among AA men (2003-2007) was 229.4/100,000 men, 60% higher than white men. AA men have the highest incidence rate in the world and are twice as likely to die of prostate cancer than whites.
2010 Census shows the U.S. population racial distribution is whites 79%, African Americans 13.8%, Asicans 4% and Hispanic ethnicity is reported at 12.5%.
The seven articles chosen from the 379 articles retrieved as meeting inclusion criteria for determination of the effectiveness of PSA screening (Table 1) are derived from predominantly Caucasian men of northern or western European heritage (predominantly Scandinavia). Several of these studies re-analyze the same cohorts or portions of previously reported cohorts. Thus, the data is mainly derived from the ERSPC and PLCO studies. The PLCO study was the only one to include American men and to report race/ethnicity. It included African Americans (4.5%), Asians (4.0%), Hispanics (2.1%) and Pacific Islanders/Native Americans (0.8%) and thus is not fully representative of the U.S. population. This same study has been oft criticized due to the contamination of the control group (those not undergoing PSA testing within the study) of whom 44% had undergone a PSA blood test prior to enrolling, and 52% who had PSA testing done outside the study during follow-up.
I remain unconvinced that these recommendations are applicable to anyone other than Scandinavian men over the age of 50 years. Adopting them without considering the increasing racial diversity of the American population seems unwise.
Sigrid V.Carlsson, MD PhD, Andrew Vickers, Hans Lilja, and Jonas Hugosson
Department of surgery (Urology), Memorial Sloan-Kettering Cancer Center, New York, U.S.A
October 26, 2011
Errors of fact, statistics and interpretation in the USPSTF review on prostate cancer screening
By giving a grade of "D" for prostate cancer screening, the U.S. Preventive Services Task Force (USPSTF) concluded that "there is moderate or high certainty that [prostate cancer screening] has no net benefit or that the harms outweigh the benefits". We have sympathy with the recommendations against current screening practices in the U.S. However, the report from the USPSTF contained important errors of fact, interpretation or statistics.
Firstly, the largest trial of PSA screening, the European Randomized study of Screening for Prostate Cancer (ERSPC) has not yet reported at its pre-specified main follow-up time. To draw conclusions that screening results "in small or no reduction in prostate cancer-specific mortality", suggests that definitive conclusions of no benefit can be drawn from an ongoing trial with ambiguous results at interim follow-up. Further, data on overall mortality from early follow-up of a screening trial cannot be used to conclude that "screening does not save lives" as screening trials lack necessary statistical power to address this issue.
The USPSTF conclusions appear importantly based on the validity of the pooling in two meta-analyses. The two largest and most high-quality studies are the U.S. Prostate, Lung, Colorectal and Ovarian Cancer trial (PLCO) and the ERSPC. However, PSA-testing was widespread before the PLCO trial and in the control group throughout the study. Therefore, the authors of this trial stated that the trial "would not be able to answer the question of whether that level of opportunistic screening is conveying a mortality benefit over no screening". Contamination in ERSPC was less than 15%. It is very hard to justify combining a trial of opportunistic vs. systematic screening with a trial of systematic vs. no screening and then calculate an "average" effect.
The USPSTF authors state "48 men received treatment for every prostate cancer-specific death prevented". This is false: the number was calculated from the number of men diagnosed, not the number treated. Moreover, this statistic depends on the length of follow-up. Models have estimated this ratio to be around 20 at 12 years of-follow-up in the ERSPC; the empirical estimate from the Goteborg trial with 14 years of follow-up is 12.
In conclusion, although fair-quality trials have demonstrated an ability of screening to prevent prostate cancer death by 20-44%[4,5], it is not unreasonable to recommend against the current modality to practice PSA screening based on the harms associated with over-diagnosis and risk of toxicity associated with treatment.
[1.] Pinsky PF, Blacka A, Kramer BS, Miller A, Prorok PC, Berg C. Assessing contamination and compliance in the prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Clinical trials. 2010;7(4):303-311.
[2.] Schroder FH, Roobol MJ. ERSPC and PLCO prostate cancer screening studies: what are the differences? Eur Urol. 2010;58(1):46-52.
[3.] Loeb S, Vonesh EF, Metter EJ, Carter HB, Gann PH, Catalona WJ. What is the true number needed to screen and treat to save a life with prostate -specific antigen testing? J Clin Oncol. 2011;29(4):464-467.
[4.] Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. 2010;11(8):725-732.
[5.] Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate- cancer mortality in a randomized European study. N Engl J Med. 2009;360(13):1320-1328.
Conflict of Interest: Dr. Hans Lilja holds patents for free PSA, hK2, and intact PSA assays. Authors affiliations: 1. Sigrid Carlsson MD PhD, Department of surgery (Urology), Memorial Sloan-Kettering Cancer Center, New York, U.S.A. and Department of Urology, Sahlgrenska Academy at Goteborg University, Goteborg, Sweden. 2. Andrew Vickers Ph.D. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY. 3. Hans Lilja MD PhD Attending, Departments of Laboratory Medicine, Surgery (Urology), and Medicine (GU-Oncology), Memorial Sloan-Kettering Cancer Center, New York, USA and Professor (adjunct) Department of Laboratory Medicine, Lund University, Sweden, and Institute of Biomedical Technlogy, University of Tampere, Finland 4. Jonas Hugosson. MD, PhD, Professor, Department of Urology, Sahlgrenska Academy at Goteborg University, Goteborg, Sweden
RogerChou, Associate Professor of Medicine, Jennifer M. Croswell
Oregon Health & Science University
January 18, 2012
In response: We appreciate the interest by Carlsson and colleagues, Hudson, and Feldstein in our review. First, we would like to clarify that the purpose of the review was to synthesize the evidence on benefits and harms of prostate cancer screening , not to make recommendations about screening. The article was not authored by the U.S. Preventive Services Task Force (USPSTF), but was commissioned and used by the USPSTF to inform its separate draft recommendation.
Carlsson and colleagues incorrectly state that the review's conclusions are based upon the results of two published meta-analyses. In fact, our review reports and summarizes the results of the two major screening trials (the European Randomized study of Screening for Prostate Cancer [ERSPC] and the Prostate, Lung, Colorectal, and Ovarian cancer [PLCO] study) separately, with the range of potential benefits, as well as a discussion of the methodological limitations of the trials and potential reasons for discrepancies in their findings. The number needed to treat of 48 was presented as reported by the ERSPC authors, and based on the number of patients who were diagnosed with prostate cancer and received treatments including surgery, radiation therapy, and watchful waiting/active surveillance (the minimum standard of care). Excluding patients who received watchful waiting, the number needed to treat would be about 40. Finally, our article clearly described the duration of follow-up in the screening trials and noted that longer follow-up may be necessary to fully understand potential benefits of screening.
We agree with Hudson that robust data on benefits of screening in certain populations such as African-American men are lacking. However, the large-scale randomized trials provide the current best evidence on potential benefits of screening. In addition, even through screening of populations with a higher prevalence of prostate cancer may result in additional diagnoses, this would not necessarily result in greater benefits relative to harms, because more men would also be subjected to harms related to diagnosis and treatment.
Feldstein points out that metastatic prostate cancer was not evaluated as an outcome in our review. Stage shift is considered an intermediate outcome to prostate cancer mortality and therefore not heavily weighted in USPSTF reviews. Fully understanding effects of screening on metastatic prostate cancer would require assessment of effects of metastatic disease on quality of life (which might be offset by negative effects related to treatment harms); such data were not provided in the screening trials.
1. Chou, R., et al., Screening for prostate cancer: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2011;155:762-71.
2. Schroder, F.H., et al., Screening and prostate-cancer mortality in a randomized European study. New Engl J Med 2009;360:1320-8.
3. Andriole, G.L., et al., Mortality results from a randomized prostate- cancer screening trial. New Engl J Med 2009;360:1310-19.
The authors received funding from the Agency for Healthcare Research and Quality to conduct the review on prostate cancer screening.
Chou R, Croswell JM, Dana T, Bougatsos C, Blazina I, Fu R, et al. Screening for Prostate Cancer: A Review of the Evidence for the U.S. Preventive Services Task Force. Ann Intern Med. ;155:762–771. doi: 10.7326/0003-4819-155-11-201112060-00375
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Published: Ann Intern Med. 2011;155(11):762-771.
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