It Is Time to Stop Screening for Prostate Cancer

Vinay Prasad

doi:10.1001/jamainternmed.2014.3078

Invited Commentary

November 2014

It Is Time to Stop Screening for Prostate Cancer

Vinay Prasad, MD¹

Author Affiliations Article Information

¹Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland

JAMA Intern Med. 2014;174(11):1841-1842. doi:10.1001/jamainternmed.2014.3078

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Prostate-specific antigen (PSA) screening has been a disappointing public health strategy. The history of the PSA test will one day serve as a reminder that, although all of us in health care want to do everything possible to reduce the mortality of cancer, the early adoption of screening techniques on the basis of insufficient evidence can lead to more harm than good.

In this issue of JAMA Internal Medicine, Sammon and colleagues¹ remind us that this day has not yet arrived. Contrary to the recommendations of the US Preventive Services Task Force (USPSTF) against routine screening, the use of prostate cancer screening continues at an alarming rate. More than one-third of men in America 80 years and older are screened, more than 40% of men aged 75 to 79 years, and nearly one-half of men between and 65 and 74 years.¹ In addition, there is marked geographic variation in the rate of screening, with rates in Hawaii as high as 59.4% and in New Hampshire as low as 24.5%.¹ These results suggest that patient preferences are unlikely to account for our patterns of use. Although some patients in the sample may have been screened just prior to current recommendations, many others likely underwent screening afterward.

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September 2, 2014

Why physicians should intensify, not abandon, PSA screening

David L Keller | none

The recommendation to stop screening for prostate cancer is incorrect and will lead to a large increase in preventable cancer deaths. This monumental error was caused by the fallacy that the results of randomized, controlled trials are superior evidence to epidemiological observation, no matter how badly the trials were designed, no matter how contaminated the trial data, and without regard to the effects of intention-to-treat analysis on diminishing the measured benefits of screening. The 16 physicians and allied healthcare professionals on the USPSTF (United States Preventative Services Task Force) all hold positions of high esteem in primary-care specialties, and are expected to volunteer an average of about 4 hours of service per week. Incredibly, no urologists were enlisted to provide their crucial perspectives on PSA screening. The "D"-level recommendation against PSA screening was based on 2 poorly-designed and badly-executed clinical trials, which both generated highly corrupted data.

First of all, one must keep in mind the important epidemiological observation that, since the introduction of widespread PSA screening in the early 1990’s, there has been a 40% decrease in prostate cancer deaths. While even such powerful observational data cannot prove cause-and-effect, it also cannot be overturned by questionable results from flawed randomized trials. The two trials used by USPSTF do not withstand even casual scrutiny.

Both of the large randomized PSA screening trials were done in a manner which ignores the essential biological behavior of cancer cells, which is to grow and propagate faster than healthy cells. Both trials set a fixed threshold PSA level for biopsy (such as 4.0 ng/mL). Consider two men: the first man has a PSA of 3.9 in year 1 and a PSA of 4.1 in year 2. The second man has a PSA of 0.5 in year 1 and a PSA of 3.5 in year 2. Which man should have his prostate biopsied? Any rational physician would biopsy the second man, whose PSA rose by 700%, rather than the first man, whose PSA rose only about 5%. Yet, a study with a fixed biopsy threshold trigger of 4.0 would biopsy only the first man, who clearly is much less likely to have prostate cancer. By not including the rate of increase of PSA in the biopsy decision, both trials ignored information in the PSA which has the strongest correlation with the presence of prostate cancer.
In the U.S.-based PLCO trial, 52% of the men in the control group had off-protocol PSA screening by their private physicians, while only 86% of men in the screening group adhered to the full screening protocol. The men in the PLCO control group had an average of 2.7 PSA screening tests done off-protocol over the 6-year course of study (1). The purpose of PLCO was to compare outcomes in PSA-screened men versus non-screened men, which simply did not occur. The results of PLCO were distorted beyond recognition by mandatory intention-to-treat analysis, which assigned outcomes to each subject's original randomization group, regardless of what they did during the study. The majority of "control" subjects who actually received PSA screening by their private doctors were counted as unscreened, thus diminishing the apparent benefit of PSA screening.

The Europe-based ERSPC study, which had lower rates of protocol violations, produced data showing a significant decrease in prostate cancer mortality due to PSA screening. An ERSPC sub-study done in the city of Goteborg had a particularly low rate of off-protocol PSA testing, and showed correspondingly higher benefits in mortality reduction. The number needed to screen (NNS) to prevent one prostate cancer death at 14 years of follow-up was 293 in Göteborg, despite the fact that 24% of the men invited to be screened never showed up but were included in the intention-to-treat analysis, thus diminishing the measured benefit of screening (2).

Another flaw in the ERSPC study was the long interval between sequential PSA tests, which averaged about 4 years (3). Such a long interval of time between samples can allow the most aggressive, fast-growing cancers to evade detection while still confined to the prostate and curable. Men over 50 should have their PSA checked at least once a year for this reason, more often if fluctuations occur, which can be averaged to produce a better estimate of the baseline PSA, deviations from the baseline, and the rate of increase of PSA. The noisier a signal, the more data samples are required to characterize it accurately.

Prostate cancer kills more men every year than any other cancer except lung cancer. It is a serious threat to all men over age 50 with a life expectancy of greater than 10 years. We know that it is curable when confined to the prostate. More PSA testing, not less, is called for. Improved diagnostic techniques, such as high-resolution prostate MRI imaging, and numerical filtering of PSA values, are being developed. One final randomized trial, which includes all of these improvements, must be conducted to obtain a fair assessment of PSA screening. The problem will be to find enough men willing to forgo screening to fill the control group.

In general, a man whose PSA is 0.1 has little to fear from prostate cancer, and a man whose PSA is 100 has much to fear from prostate cancer. The problem is to clearly and accurately determine how to proceed within those 3 orders of magnitude of data. The art of medicine is to act in the best interests of the patient when the scientific facts are not perfectly understood. Clinical common sense and scientific intuition demand that we measure and carefully consider the PSA levels of men over the age of 50, pending the results of further trials. Watchful waiting is always an option, which at least provides prognostic awareness.

The results of poorly-designed and poorly-executed controlled clinical trials give the mere illusion of high-quality data. Their results should not be relied upon as a basis for treatment decisions when they contradict powerful epidemiological data and our understanding of the biological basis of the disease.

References

1: Gulati R, Tsodikov A, Wever EM, Mariotto AB, Heijnsdijk EA, Katcher J, de Koning HJ, Etzioni R. The impact of PLCO control arm contamination on perceived PSA screening efficacy. Cancer Causes Control. 2012 Jun;23(6):827-35. doi: 10.1007/s10552-012-9951-8. Epub 2012 Apr 10. PubMed PMID: 22488488; PubMed Central PMCID: PMC3556907.
2: Hugosson J, Carlsson S, Aus G, Bergdahl S, Khatami A, Lodding P, Pihl CG, Stranne J, Holmberg E, Lilja H. Mortality results from the Göteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. 2010 Aug;11(8):725-32. doi: 10.1016/S1470-2045(10)70146-7. Epub 2010 Jul 2. PubMed PMID: 20598634; PubMed Central PMCID: PMC4089887.
3: Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, Kwiatkowski M, Lujan M, Lilja H, Zappa M, Denis LJ, Recker F, Berenguer A, Määttänen L, Bangma CH, Aus G, Villers A, Rebillard X, van der Kwast T, Blijenberg BG, Moss SM, de Koning HJ, Auvinen A; ERSPC Investigators. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009 Mar 26;360(13):1320-8. doi: 10.1056/NEJMoa0810084. Epub 2009 Mar 18. PubMed PMID: 19297566.

CONFLICT OF INTEREST: None Reported

September 2, 2014

Stopping Prostate Cancer Screening?

Howard Homler MD, FACP | Private Practice, Internal Medicine

Dr. Prasad's points about prostate cancer screening are logical and evidence-based. However, the issue of 'cancer screening' is so embedded emotionally and financially in our health care system that I don't expect his recommendations to be followed anytime soon. Emotion regarding cancer is strong. I see any male patients come in for a checkup only after someone they know has recently been diagnosed or died from prostate cancer. Perhaps that cancer was found too early (via screening) or too late (by symptoms)--but the message is the same -- \"Doc, do I have prostate cancer? Aren't you going to check me for it?\" We've been inculcated so long to believe in screening and early detection that it is considered blasphemy to question it. On the side of the doctor, emotion can be strong, too. Heuristically, we are biased by the occasional cases of prostate cancer that we did pick up on DRE or PSA testing--\"Doc, you saved my life!\" and chagrined when a patient we recommended against screening goes on to get diagnosed with prostate cancer by another physician. And who can't help but be shaken seeing someone die from prostate cancer. And specialists who treat prostate cancer often see the most advanced cases--leading to a bias to treat.Financial interests shouldn't be ignored.. Even the hospital across the street from my office offers Prostate Cancer Screening Fairs, just as it does Carotid Ultrasound Screening for the general public. On TV, I see advertisements for the DaVinci Robotic Surgery for prostate (and other cancers). How is my evidenced-based spiel supposed to compete with that? Have any of you seen the publicity for proton-beam therapy for prostate cancer? Discussion about reducing screening often raise immediate concerns about HMO's or insurance companies or the government trying to save money at the expense of patients.I suspect it will take better public education to help patients understand the benefits and risks of screening. And for healthcare providers, it remains critical to understand the difference between offering screening to asymptomatic individuals and evaluating symptomatic patients.

CONFLICT OF INTEREST: None Reported

November 4, 2014

True cost of unnecessary PSA testing

William Tierney | Regenstrief Institute

At age 72, my father got a screening PSA. I begged him NOT to get it. It was 7, slightly elevated, but he had BPH with mild symptoms. I begged him NOT to go to the urologist his family physician referred him to. He went and got ten biopsies, nine of which showed BPH and one of which showed a nest of highly differentiated adenocarcinoma cells, with the entire nest (with margins) in the biopsy specimen. I begged him to do nothing. His urologist got a CT scan which was normal except for a 4 cm abdominal aortic aneurysm which the urologist said needed to be fixed. I begged him to have it followed. He got his aorta replaced. A year later, he had bilateral stenosis at the femoral artery graft insertion sites, had severe claudication, and never walked more than 30 feet again. His legs became weak and his gait unsteady through lack of use. He fell five years later, hit his head, had a cerebral bleed, and died. The urologist had opted to do nothing about his prostate. So, what was the true cost of his PSA test?

CONFLICT OF INTEREST: None Reported

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