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Editor's Note
April 2016

Use of Prostate-Specific Antigen Testing Is in the Eye of the Beholder

JAMA Intern Med. 2016;176(4):547-548. doi:10.1001/jamainternmed.2015.8104

The use of prostate-specific antigen (PSA) screening for prostate cancer is controversial. Various organizations have released conflicting messages regarding the use of the PSA screening test. In 2012, the US Preventive Services Task Force recommended against routine PSA screening, citing a lack of evidence regarding its benefits and known harms from prostate biopsy and overtreatment of indolent prostate cancer.1

In this issue of JAMA Internal Medicine, Zavaski et al2 report that since the release of the US Preventive Services Task Force statement, the rate of PSA testing has declined overall but still is performed more frequently for patients receiving PSA testing for preventive health reasons through their urologist rather than through their primary care physician. The vast majority of PSA testing is still performed by primary care physicians, but there seems to be a continued perception, more firmly held by urologists than by primary care physicians, that the screening is beneficial. Urologists may hold this belief because they have referred more men who request PSA testing or because they have seen more poor outcomes from metastatic prostate cancer. Regardless, recent data show some decline in the detection of early-stage prostate cancer, which likely reflects decreased ordering of PSA tests, and hopefully indicates avoidance of harms of cancer treatment, such as erectile dysfunction and urinary incontinence.3 We will need to await data on rates of metastatic disease and prostate cancer deaths to understand the full effect of less PSA testing. To our knowledge, such data were not available 30 years ago when the PSA blood test became available. The American Urologic Association Quality Registry was developed in 2014 to better track prostate cancer care and should produce the type of information our patients deserve.4

In the meantime, recommendations to reduce PSA screening will only strengthen with release of a Healthcare Effectiveness Data and Information Set measure5 targeting the elimination of PSA screening in men older than 70 years. It is essential that, along with improved collection of outcomes data, we also have outcomes data on the myriad novel diagnostic and risk stratification tools rapidly becoming available, such as magnetic resonance imaging or ultrasound fused-guided prostate biopsy and genomic testing. Without such evidence, we can be sure that differing entrenched beliefs between urologists and primary care physicians will only become more expensive. Meanwhile, the widespread use of the PSA test should serve as a cautionary tale of the importance of first establishing that benefit exceeds harms before recommending new cancer screening tests.

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Article Information

Conflict of Interest Disclosures: None reported.

References
1.
US Preventive Services Task Force.  Final recommendation statement: prostate cancer: screening, May 2012.http://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/prostate-cancer-screening. Accessed January 19, 2016.
2.
Zavaski  ME, Meyer  CP, Sammon  JD,  et al.  Differences in prostate-specific antigen testing among urologists and primary care physicians following the 2012 USPSTF recommendations [published online February 8, 2016].  JAMA Intern Med. doi:10.1001/jamainternmed.2015.7901.PubMedGoogle Scholar
3.
Jemal  A, Fedewa  SA, Ma  J,  et al.  Prostate cancer incidence and PSA testing patterns in relation to USPSTF screening recommendations.  JAMA. 2015;314(19):2054-2061.PubMedGoogle ScholarCrossref
4.
American Urological Association.  AUA Quality Registry (AQUA).https://www.auanet.org/resources/aqua.cfm. Accessed January 5, 2016.
5.
National Committee for Quality Assurance.  Proposed new measures for HEDIS 2015: colorectal and prostate cancer appropriateness/overuse measures. http://www.ncqa.org/Portals/0/HomePage/Overuse_Materials.pdf. Published 2014. Accessed December 30, 2015.
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    2 Comments for this article
    EXPAND ALL
    The PSA: tossing out the baby with the bathwater
    Stephen B. Strum, MD, FACP | Private Practice of Medical Oncology
    I am a medical oncologist that decided to subspecialize in prostate cancer (PC) in 1983. My experience with this disease spans 33 years and thousands of patients with PC, including the pre-PSA and PSA eras. Initially, the men I evaluated almost always had far advanced disease, with bone and/or nodal metastases and often lung, liver and even CNS spread. This became a rarity with routine PSA testing and the stage migration of PC shifted dramatically away from bulky disease (T3,T4) to PSA only related disease, even with a normal digital rectal exam (T1c).

    Now, because physicians irrationally subjected
    men with low volume disease to ablative therapies associated with significant morbidity & healthcare costs, we have thrown out the most important biologic marker for the most common malignancy in men: the PSA. We did not look at the opportunities that such an early diagnosis afforded us:
    1. Changing diet, lifestyle, & other epigenetic factors to turn PC in low volume disease into a chronic condition which has no effect on mortality or morbidity.
    2. Use the diagnosis of PC as a red flag insofar as PC-related illnesses e.g. osteoporosis, dyslipidemias, pro-inflammatory states, cardiovascular disease, lower urinary tract symptoms, etc.
    3. Use the diagnosis of PC as a risk factor for other related cancers in the patient and in siblings, & children such as PC, breast cancer, colorectal cancer.

    Instead of educating patients and physicians on how to assess tumor volume and extent, and the ramifications of a diagnosis of PC, we simply tossed out the \"baby\" (PSA) & essentially equated this crucial biomarker as something easily disposable (the bathwater).
    CONFLICT OF INTEREST: None Reported
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    PSA screening for prostate cancer has never been properly evaluated
    David L. Keller, MD, FACP | independent
    The two randomized trials of PSA screening upon which the USPSTF based their D recommendation were ERSPC and PLCO. PLCO suffered from such high rates of statistical contamination (including off-protocol and pre-protocol screening of control subjects) that its negative result is not considered a valid assessment of PSA screening. [1]

    ERSPC reported a reduction in the prostate cancer mortality rate for screened men of 27% at 13 years by per-protocol analysis [2], versus a 21% reduction by intention-to-treat analysis. There is a 6% discrepancy between these mortality reduction estimates because the latter counts men as having been screened
    based only on their initial randomization, even if they never had a single PSA test. Many consider the former figure a more realistic estimate for patients who actually get screened as directed.

    The high false-positive rate of PSA screening led to many unnecessary negative biopsies in the randomized trials. In clinical practice, the common-sense response to a high PSA is to repeat the test a week later for confirmation, because there are many benign causes of transient PSA elevation. If the repeated PSA is normal, the patient can be spared a biopsy. This approach has been demonstrated to reduce the harms of PSA screening compared with reflex biopsy based on a single elevated PSA level, as practiced in the randomized trials. [3]

    PSA velocity was not considered in the biopsy decision. For example, in centers using a biopsy threshold PSA of 3, a man whose PSA rose from 2.9 to 3.1 (a 6% increase) was biopsied, but a man whose PSA rose from 0.5 to 2.5 (a 400% increase) was not biopsied. A rapidly rising PSA is more likely to signal an aggressive prostate cancer than a higher but essentially stable PSA.

    Most subjects were screened with a PSA test about every 4 years in ERSPC, an interval long enough to allow the most aggressive tumors to metastasize before being detected. In clinical practice, annual PSA measurements can establish a baseline PSA range, allow for calculation of PSA velocity, and perhaps permit detection of worrisome increases quickly enough to intervene before metastasis occurs. Additional information itself cannot harm the patient, only its misuse can.

    PSA screening has been associated with a 40% decrease in mortality from prostate cancer [4], which no other intervention or population trend can explain. Given the discordance between the large benefit associated with PSA screening observed in populations, versus the smaller or absent benefit seen in demonstrably flawed controlled studies, it would be foolish to abandon the one measure (PSA screening) most likely to have caused all or most of the decrease in prostate cancer mortality. After all, we advise against smoking based on observational data, in the complete absence of randomized trial data.

    It was folly for the USPSTF to issue their anti-PSA dictum without a single urologist on their panel. As the ban on PSA testing is enforced, conservative models predict that discontinuing PSA screening for all men may generate many avoidable cancer deaths. Continuing PSA screening for men aged <70 years could prevent greater than one-half of these avoidable cancer deaths while dramatically reducing over-diagnosis compared with continued PSA screening for all ages. [5] If these models are correct, USPSTF will not be able to undo the harms done by their recommendation against PSA screening.

    Harms associated with prostate cancer treatments, such as erectile dysfunction and urinary incontinence, have been steadily reduced by improvements in conformal radiation, brachytherapy, robotic surgery, imaging and watchful waiting. Men should be given a choice whether to have PSA screening. Such a choice requires thorough discussions with patients and more effort by clinicians to carefully track PSA levels over time, with the goal of maintaining or improving the reductions we have achieved in prostate cancer mortality by means of PSA screening.

    References

    1: Vickers AJ. Does Prostate-Specific Antigen Screening Do More Good Than Harm?: Depends on How You Do It. JAMA Oncol. 2016 Mar 24. doi: 10.1001/jamaoncol.2015.6276. [Epub ahead of print] PubMed PMID: 27010733.

    2: Schröder FH and ERSPC Investigators. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of
    follow-up. Lancet. 2014 Dec 6;384(9959):2027-35. doi:10.1016/S0140-6736(14)60525-0.
    Epub 2014 Aug 6. PubMed PMID: 25108889; PubMed Central PMCID: PMC4427906.

    3: Lavallée LT, Binette A, Witiuk K, Cnossen S, Mallick R, Fergusson DA, Momoli F, Morash C, Cagiannos I, Breau RH. Reducing the Harm of Prostate Cancer Screening: Repeated Prostate-Specific Antigen Testing. Mayo Clin Proc. 2016 Jan;91(1):17-22. doi: 10.1016/j.mayocp.2015.07.030. Epub 2015 Dec 10. PubMed PMID: 26688045.

    4: Howlader N, Noone AM, Krapcho M et al: SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER web site, April 2012

    5: Gulati R, Tsodikov A, Etzioni R, Hunter-Merrill RA, Gore JL, Mariotto AB, Cooperberg MR. Expected population impacts of discontinued prostate-specific antigen screening. Cancer. 2014 Nov 15;120(22):3519-26. doi: 10.1002/cncr.28932. Epub 2014 Jul 25. PubMed PMID: 25065910; PubMed Central PMCID: PMC4221407.
    CONFLICT OF INTEREST: None Reported
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