Articles

Platinum Opinion

It Ain’t What You Do, It's the Way You Do It: Five Golden Rules for Transforming Prostate-Specific Antigen Screening

By: Andrew Vickers a lowast , Sigrid Carlsson b c , Vincent Laudone b and Hans Lilja b d e

European Urology, Volume 66 Issue 1, August 2014, Pages 188-190

Published online: 01 August 2014

Abstract Full Text Full Text PDF (1,2 MB)

Take Home Message

The benefit–harm ratio of PSA screening can be dramatically improved by avoiding screening, biopsy and treatment in men who are unlikely to benefit, and by referring men that do need treatment to high volume centers.

Early detection of prostate cancer by means of prostate-specific antigen (PSA) testing of asymptomatic men remains subject to debate. Commentators discuss the evidence as to whether screening actually reduces prostate cancer mortality and, if so, whether the extent of mortality reductions outweighs the harms of overdiagnosis and overtreatment.

The difficulty with this sort of debate is that it appears to assume that PSA is a single intervention. However, estimates for the effects of PSA screening are subject to important variations because PSA screening can be done in different ways in terms of the criteria and procedures for screening, biopsy, and treatment. For instance, it seems reasonable to suppose that PSA screening would do far more harm than good were we to focus on screening men >80 yr of age, have liberal criteria for biopsy, aggressively treat men who have low-risk disease or a short life expectancy, undertreat high-risk disease, and treat predominantly in low-volume settings. “Screening better” means avoiding such an approach. In this paper, we present five golden rules for PSA screening that importantly and favorably will shift the ratio of benefits to harms [1] .

Despite guidelines emphasizing shared decision making, many doctors order the PSA test without discussing it with the patient [2] . PSA often appears to be a test added when a doctor orders some blood work as part of a regular health checkup, for example. On straightforward ethical grounds, we believe that doctors should not order a PSA test, perhaps unique among blood tests in terms of its downstream consequences, without, at the very least, informing the patient about the uncertain balance between the benefits versus harms, providing a rationale in terms of why screening could do more harm than good for that individual patient, and obtaining explicit verbal consent before proceeding to order the PSA test.

2. Golden Rule 2. Don’t screen men who won’t benefit

Prostate cancer is generally a slow-growing disease, and the benefits of screening take considerable time, no less than 10–15 yr, to accrue. Currently, men are being screened who are dying from other cancers [3] or who are age 80 and have multiple comorbidities [4] . PSA screening in such men is highly unlikely to have any benefit but may lead to harm. There is some variation as to the criteria for ending screening. Age 75 is used as a stopping point in several recommendations, although statistical modeling has shown that any reductions in mortality associated with screening men in their 70s are offset by reductions in quality of life [5] . There is also evidence that men can stop in their 60s if PSA is <1 ng/ml [6] and [7], close to the median at this age. But although guidelines vary, there is also clear agreement that men >75 yr of age should be screened only in special circumstances and that men with multiple comorbidities and a life expectancy <10 yr should be exempted from PSA screening.

3. Golden Rule 3. Don’t biopsy without a compelling reason

Most men with a modestly elevated PSA do not have prostate cancer, and very few men with a low PSA have aggressive disease [6] and [8]. Accordingly, biopsies should not automatically be considered for a modestly elevated PSA without further work-up for benign disease including digital rectal examination, a repeat PSA after a few weeks [9] , and consideration of reflex tests such as the free-to-total PSA ratio [10] . Similarly, biopsy should not be considered for men with a PSA below typical biopsy thresholds such as 3 ng/ml, with the exception of a clearly abnormal digital rectal examination conducted for cause (such as urinary symptoms) or during a work-up for other reasons, such as colonoscopy. A screening digital rectal examination [11] has been shown to have a very low positive predictive value in men with low PSA, as has PSA velocity [12] .

4. Golden Rule 4. Don’t treat low-risk disease

Many men with screen-detected cancer have Gleason score 6 disease, a phenotype associated with a very low risk of cancer-specific mortality. Such men do not generally need immediate curative treatment and can be safely managed initially by active surveillance [13] . One important limitation of this approach is that criteria for active surveillance, or switching to definitive treatment, are yet to be firmly established. Contemporary criteria used have often been restrictive, such as requiring that disease be nonpalpable, changes in PSA levels over time are extremely small, or that a very low number of biopsy cores are involved [14] . In the PIVOT trial [15] , the risk of death in patients with low-risk disease managed conservatively was very low. Mortality was not reduced by surgery, and the upper bound of the confidence interval excluded a large absolute risk reduction. Yet many of these low-risk men would have multiple positive cores or >50% involvement of one core.

5. Golden Rule 5. If you have to treat, do so at a high-volume center

Convincing evidence indicates that experienced surgeons have higher cure rates, lower complication rates, and better outcomes for urinary and erectile function [16] . There is also convincing evidence that many patients are treated by low-volume surgeons. The learning curve for radical prostatectomy has been estimated to be at least 250 procedures [17] . Yet among urologists who treat prostate cancer, the median annual volume is three, with more than a quarter conducting only a single radical prostatectomy per year [18] .

6. Conclusions

PSA screening is often thought to be a problem for primary care providers. Yet urologists are the gatekeepers for all downstream effects of PSA testing. Consider a 83-year-old man referred to the local urologist due to a finding of an elevated PSA test (5 ng/ml) where the urologist recommended not to conduct a biopsy, sending a note back to the primary care physician explaining that the patient had no urinary symptoms, had no suspicious findings at digital rectal examination, was not in need of urologic care, that PSA screening was not of value in a man of that age, and that a moderately elevated PSA alone was not a strong indication for biopsy in an older man. Or consider if more urologists told prostate cancer patients, “I have been a urologist for a long time, and I am good at what I do. But you have prostate cancer, and cancer treatment is very specialized. So I am going to refer you to a comprehensive cancer center for your treatment. I’ll keep in contact with them and monitor your progress.”

In summary, primary care physicians and urologists need to collaborate and take a more active role in ensuring that PSA screening does more good than harm for the individual requesting the PSA test. Following the five golden rules described here is a first step in ensuring that it does.

Conflicts of interest

Hans Lilja holds patents for free PSA, hK2, and intact PSA assays, and he is named, along with Andrew Vickers, on a patent application for a statistical method to detect prostate cancer.

Funding support

This study was supported by National Cancer Institute (R01CA160816, R01 CA175491, and P50-CA92629), the Sidney Kimmel Center for Prostate and Urologic Cancers, and David H. Koch through the Prostate Cancer Foundation, the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Program.

References

  • [1] S. Carlsson, A.J. Vickers, M. Roobol, et al. Prostate cancer screening: facts, statistics, and interpretation in response to the US Preventive Services Task Force Review. J Clin Oncol. 2012;30:2581-2584 Crossref
  • [2] R.J. Volk, S.K. Linder, M.A. Kallen, et al. Primary care physicians’ use of an informed decision-making process for prostate cancer screening. Ann Fam Med. 2013;11:67-74 Crossref
  • [3] C.S. Sima, K.S. Panageas, D. Schrag. Cancer screening among patients with advanced cancer. JAMA. 2010;304:1584-1591 Crossref
  • [4] M.W. Drazer, D. Huo, M.A. Schonberg, A. Razmaria, S.E. Eggener. Population-based patterns and predictors of prostate-specific antigen screening among older men in the United States. J Clin Oncol. 2011;29:1736-1743 Crossref
  • [5] E.A. Heijnsdijk, E.M. Wever, A. Auvinen, et al. Quality-of-life effects of prostate-specific antigen screening. N Engl J Med. 2012;367:595-605 Crossref
  • [6] A.J. Vickers, A.M. Cronin, T. Bjork, et al. Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study. BMJ. 2010;341:c4521 Crossref
  • [7] P.J. van Leeuwen, D. Connolly, T.L. Tammela, et al. Balancing the harms and benefits of early detection of prostate cancer. Cancer. 2010;116:4857-4865 Crossref
  • [8] I.M. Thompson, D.K. Pauler, P.J. Goodman, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. N Engl J Med. 2004;350:2239-2246 Crossref
  • [9] J.A. Eastham, E. Riedel, P.T. Scardino, et al. Variation of serum prostate-specific antigen levels: an evaluation of year-to-year fluctuations. JAMA. 2003;289:2695-2700 Crossref
  • [10] R. Lee, A.R. Localio, K. Armstrong, S.B. Malkowicz, J.S. Schwartz, Free PSA Study Group. A meta-analysis of the performance characteristics of the free prostate-specific antigen test. Urology. 2006;67:762-768 Crossref
  • [11] C. Gosselaar, M.J. Roobol, S. Roemeling, F.H. Schröder. The role of the digital rectal examination in subsequent screening visits in the European randomized study of screening for prostate cancer (ERSPC). Rotterdam. Eur Urol. 2008;54:581-588 Crossref
  • [12] A.J. Vickers, C. Till, C.M. Tangen, H. Lilja, I.M. Thompson. An empirical evaluation of guidelines on prostate-specific antigen velocity in prostate cancer detection. J Natl Cancer Inst. 2011;103:462-469 Crossref
  • [13] L. Klotz, L. Zhang, A. Lam, R. Nam, A. Mamedov, A. Loblaw. Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol. 2010;28:126-131 Crossref
  • [14] A.C. Reese, P. Landis, M. Han, J.I. Epstein, H.B. Carter. Expanded criteria to identify men eligible for active surveillance of low risk prostate cancer at Johns Hopkins: a preliminary analysis. J Urol. 2013;190:2033-2038 Crossref
  • [15] T.J. Wilt, M.K. Brawer, K.M. Jones, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012;367:203-213 Crossref
  • [16] J.A. Eastham. Do high-volume hospitals and surgeons provide better care in urologic oncology?. Urol Oncol. 2009;27:417-421 Crossref
  • [17] A.J. Vickers, F.J. Bianco, A.M. Serio, et al. The surgical learning curve for prostate cancer control after radical prostatectomy. J Natl Cancer Inst. 2007;99:1171-1177 Crossref
  • [18] C.J. Savage, A.J. Vickers. Low annual caseloads of United States surgeons conducting radical prostatectomy. J Urol. 2009;182:2677-2679

Footnotes

a Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

b Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

c Department of Urology, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden

d Departments Medicine and Laboratory Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

e Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK

lowast Corresponding author. Memorial Sloan Kettering Cancer Center, 307 East 63rd Street, 2nd Floor, New York, NY 10065, USA.

Place a comment

Your comment *

max length: 5000