Expert Urges Revisiting PSA Screening After Pivotal Trial Update

Jim C. Hu, MD

After updated findings from the landmark Prostate, Lung, Colorectal, and Ovary (PLCO) screening trial were presented earlier this year, members of the oncology community strongly suggested that the United States Preventative Services Task Force (USPSTF) revise its views on prostate-specific antigen (PSA) screening for patients with prostate cancer.

Originally launched in 1993, the PLCO trial involved 77,000 men with an average risk of prostate cancer who were randomized to annual PSA screening for 6 years and digital rectal exam for 4 years or no screening for prostate cancer. At a follow-up of 7 years, it was determined that there was no difference in prostate cancer detection or mortality between the screening and control groups.¹

These data were instrumental in the recommendation made by the USPSTF against PSA screening.

However, an updated analysis of the study showed that 80% of the control group reported at least 1 PSA test during the trial.² Additionally, more than half had PSA assessments within the year prior to enrollment, and 70% reported having a PSA test in the 2 years prior to joining the control group of the trial. These results demonstrate that the original comparisons cannot be interpreted—and that PSA does indeed have a role—the authors noted.

“We shouldn’t bury PSA yet; this is kind of a ‘smoking gun’ for the demise of PSA,” says study author Jim C. Hu, MD. “We did more investigative work to really look at the study design and found that there was more contamination than there originally was, which, unfortunately, makes the PLCO study uninterpretable. Therefore, any conclusions drawn from that, any policy made as of results to that study, should really be rethought.”

OncLive: What are some of the challenges associated with PSA screening?

In an interview with OncLive, Hu, the Ronald P. Lynch Professor of Urologic Oncology at Weill Cornell Medicine and NewYork-Presbyterian Hospital, sheds light on the updated PLCO findings and what this means for the role of PSA in the field of prostate cancer.Hu: PSA testing was introduced in the early 1990s, and it certainly led to an increased incidence. We found more prostate cancers, and we found that the prostate cancer—specific mortality went down—roughly by 50% compared with pre-PSA.

We also saw a decrease in the likelihood of metastatic disease at surgery. For instance, before PSA testing, about 30% of men who went to surgery had cancers that had gone to the lymph nodes—that has now decreased to about 2% to 3% after adoption of PSA testing.

PSA, on average, has shown that it may detect prostate cancers about 7 to 12 years before they were detected previously. This means that the lead-time bias for detecting cancers is much earlier. This then leads to catching what we already know could be indolent or slow-growing prostate cancers.

What happened with the original PLCO trial, and why does it need to be revaluated?

Although it leads to earlier detection of prostate cancer, it also detects a lot of indolent tumors that leads to an overdiagnosis and overtreatment issue, as some men may not understand the tumor biology, and the risks associated with watching it versus getting a biopsy. This is why it has been controversial.The original study randomized men to PSA testing annually for 6 years versus no testing whatsoever. At the end of the trial follow-up—after about 9 to 10 years—they did not see a difference in prostate cancer-specific mortality. The conclusion of the trial was that PSA testing does not lessen prostate cancer¬—specific mortality.

However, in the same issue of The New England Journal of Medicine, the results of a European study were published.³ It was about twice as large in study design; PSA testing wasn’t conducted annually, but every 4 years. In that study, there was a 21% decrease in prostate cancer mortality.

Why was the European trial showing 1 thing, and nothing in the American study? As the investigators reported in 2009, there was 52% contamination in the control arm—which was comprised of the men who were randomized to not have PSA testing. Many of us felt that this study was really a comparison of annual testing versus occasional testing because of that 52% contamination.

The USPSTF, which reviews a lot of screening guidelines for other issues, looked at all the evidence originally in 2011 and finalized the recommendation in 2012, giving PSA testing a grade D recommendation. This means that there was fairly good evidence that PSA testing didn’t do much good.

What did you find?

The relevance of our study is that the PLCO released their data publicly for re-analysis or secondary analyses. We had the opportunity then to question why 1 study was negative and the European study was positive.By going back and looking at these surveys used to assess PSA screening, we found that close to 90% of the control arm—the patients who were not supposed to get PSA testing—actually got PSA testing cumulatively during the study period. In fact, in later years, the amount of PSA testing in the control arm was greater than the intervention arm. It was really a comparison of very similar exposure to PSA testing in both arms.

Should PSA testing continue to be utilized?

Our hope is that the USPSTF reassesses the utility of PSA testing in men’s health. With the evidence we have provided, the PLCO study is uninterpretable; therefore, we have to look at the randomized trial from Europe and the epidemiology data from the United States.The question for additional research is, “What is the frequency for PSA testing?” Every man should be offered a PSA test. After the study findings, there were medical guidelines that suggested that this should be shared decision-making. In the doctor’s office—primarily with internists and family practitioners—there should be a discussion where patients will be educated about the risks and benefits, and then a shared decision-making or consensus should be made on whether men should get the test or not.

The challenge with shared decision-making, although it’s obviously the ideal way to do things, is that the dollars in medicine are decreasing. The vast majority of Americans don’t have access to this type of care and we are in a situation where physicians are having to see more patients in a shorter amount of time, so it’s harder to make an informed decision.

However, telling everyone that they should get PSA screening has become controversial. If you waive the evidence, there is still strong evidence that PSA testing in a patient’s late 40s is helpful in determining their lifetime risk of getting prostate cancer. That should then determine the frequency and intensity of screening beyond the age of 50.

You must hear about overtreatment often. What is the solution to avoiding this with regard to PSA testing?

One of the good things about this study is that we recognized that there was overtreatment of prostate cancer, overdiagnosis of disease, and there is now a greater use of active surveillance for lower risk disease. Those are all good, unintended side effects or downstream consequences of the study. However, to say that there is no benefit to PSA testing as the original findings suggested in 2009 is untrue—based on the previously unrecognized severe limitations we found.How do we develop better decisional tools to develop better shared decision-making? Also, in these past 5 or 6 years, the practice of diagnosing prostate cancer has changed, meaning that there are more genetic tests for biomarkers available. There are imaging advances that have been made in terms of MRI and MRI-targeted biopsies.

Before actually doing a biopsy, we are getting a more accurate presentation of what the risk is for a patient to develop a clinically significant prostate cancer. Are we where we ultimately need to be? I don’t think so, but I think the aspects of personalized medicine through biomarkers as well as imaging is improving and moving in the right direction. I don’t believe those modalities replace PSA testing— they supplement them.

Overall, PLCO is a landmark study. It really armed the medical professional guidelines to say that there is little value to PSA testing. Although it is still controversial how frequently we should give it, when we to start, and what the follow-up steps are before doing a biopsy, these are things we are still studying. Right now, the rest is still of value, because PSA is associated with 21% reduction in the prostate cancer-specific mortality, as seen in the European study.

References

1. Andriole GL, Crawford ED, Grubb RL, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310-1319.
2. Shoag J, Mittal S, Halpern J, et al. Reevaluating PSA testing rates in the PLCO trial. Presented at: 2016 American Urological Association Annual Meeting; May 6-10, 2016; San Diego, CA. Abstract 1140.
3. Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320-1328.