Active surveillance, physician–patient communication may redefine role of PSA testing

Most men diagnosed with prostate cancer will not die of the disease.

Even so, it remains the second-leading cause of cancer mortality among American men, accounting for an estimated 26,120 deaths last year.

That paradox has urologists and policymakers debating the value of PSA screenings and the frequency with which they should be administered.

In 2008, the U.S. Preventive Services Task Force (USPSTF) recommended against PSA–based screening for men aged older than 75 years. Four years later, the panel broadened its recommendation to include all men based on the belief that the benefits of annual testing do not outweigh the potential harms — such as infection, incontinence and impotence — associated with treatment.

That recommendation — which the task force intends to update this year — created a chasm between clinicians who think less testing will result in higher incidence of metastatic prostate cancer, and those who believe too many men are unnecessarily treated for indolent or slow-growing disease.

Photo courtesy of David F. Penson, MD, MPH.

“There has been a drop in the number of new cases of prostate cancer since the USPSTF recommendation in 2012,” David F. Penson, MD, MPH, chair of the department of urologic surgery at Vanderbilt University School of Medicine, told HemOnc Today. “If you look at the survey data, [the decline in diagnosis] is because of a drop in PSA screening.

“Now, the question becomes: What does it mean?” Penson added. “It’s too early to know for sure.”

HemOnc Today spoke with urologic oncologists about the potential consequences of less PSA testing, the harms of overdiagnosis, the increased use of active surveillance among men with low-risk disease, and whether risk factors such as race should be considered when creating screening guidelines.

Benefits of screening

The USPSTF based its 2012 recommendation primarily on the contradictory results of two randomized studies published in 2009.

In the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, Andriole and colleagues reported that — after 7 years of follow-up — death rates did not differ between men who received annual screening with PSA testing or digital rectal exams (2 deaths per 10,000 person-years) and those who received usual care (1.7 deaths per 10,000 person-years). The study also underscored the harms associated with follow-up biopsies, radiation and surgery.

In the European Randomized Study of Screening for Prostate Cancer (ERSPC), Schröder and colleagues determined that — after 9 years of follow-up — screenings reduced prostate cancer death rates by 20% (RR = 0.8; 95% CI, 0.65-0.98). The absolute risk difference was 0.71 per 1,000 men, indicating that 1,410 men would need to be screened and 48 prostate cancer cases would need to be treated to avert one death.

Following the results of those population-based trials, Otis W. Brawley, MD, MACP, chief medical officer at the American Cancer Society, openly questioned the benefits of PSA screenings.

“The average man who gets screened is 48 times more likely to be harmed by screening than he is to be saved by screening at 9 years after diagnosis,” Brawley told HemOnc Today in 2011.

The ERSPC projections changed dramatically after longer follow-up, showing a substantially increased benefit of screening. At 13 years, the number of men who needed to be screened to prevent a single prostate cancer death decreased from 1,410 to 781, and the number of men needed to be diagnosed to prevent a single death decreased from 48 to 27.

Results also showed PSA screening reduced prostate cancer mortality risk by 27% (RR = 0.73; 95% CI, 0.61-0.88), and suggested men aged 55 to 69 years are the most likely to benefit from screening. Screening did not reduce mortality in other age groups.

After 13 years of follow-up of the PLCO trial, men who underwent annual prostate cancer screening had a 12% higher incidence of prostate cancer than men who received usual care (RR = 1.12; 95% CI, 1.07-1.17). Additionally, the two groups had the same rate of death from the disease (3.7 vs. 3.4 deaths per 10,000 person-years; RR = 1.09; 95% CI, 0.87-1.36), and there was no evidence of a mortality reduction with PSA screenings.

There are shortcomings in both the PLCO and the ERSPC studies, Brawley said.

For example, a subsequent analysis by Pinsky and colleagues showed 52% of men in the control arm of the PLCO trial had at least one PSA test during the study period; the median number of PSA tests was 2.74 in the control arm and 5 in the screening arm, prompting some to question the validity of the comparison.

Brawley, a HemOnc Today Editorial Board member, acknowledged the trend toward less aggressive treatment of early-stage prostate cancer has softened his stance on screenings.

“I am much warmer toward screening within the physician–patient relationship, where there is an understanding of a potential for benefit and a potential for risk, than I was even 4 years ago,” Brawley told HemOnc Today. “Quite honestly, I look at the American Cancer Society recommendation from 2010. They said men should be offered the test, informed of the potential risks and potential benefits, and be encouraged to make a decision. I think that’s wise.”

Nearly half of all men with localized prostate cancer are now candidates for observation, Brawley said.

“That makes [PSA screening] a lot more palatable,” he said. “I’m getting friendlier toward screening, because we might be able to help [rather] than hurt more men with screening.”

The USPSTF is updating its recommendation as part of its “normal process,” task force chair Kirsten B. Bibbins-Domingo, MD, PhD, MAS — endowed chair of medicine and professor of epidemiology and biostatistics at University of California, San Francisco — told HemOnc Today.

“The task force considers updating recommendations after 5 years — particularly in areas of active research — so that the new evidence published in the intervening years can be incorporated,” Bibbins-Domingo wrote in an email.

The task force began updating its recommendation in 2015, and it published a final research plan in April 2016. Its next step is to issue a draft recommendation statement and evidence review that will be available for public comment.

“The task force aims to move each topic through the recommendation development process efficiently, while allowing the time necessary to incorporate critical input from our expert methodologists, reviewers and the general public,” Bibbins-Domingo wrote.

Contradictory studies

Contradictory results from studies designed to examine the effects of the USPSTF’s 2012 decision have created confusion.

In a 2015 study published in JAMA, Ahmedin Jemal, DVM, PhD, vice president of surveillance and health services research at ACS, and colleagues evaluated screening rates for 18,385 men aged 50 years and older who responded to the National Health Interview Survey. The percentage of men who reported having been screened during the previous year peaked at 40.6% in 2008, then declined to 37.8% in 2010 and 30.8% in 2013.

When researchers examined prostate cancer incidence between 2005 and 2012, they determined the largest year-over-year decline (16%) occurred between 2011 and 2012.

In a subsequent study published last year in JAMA Oncology, Jemal and colleagues reported that incidence of distant-stage metastatic disease had not changed significantly between 2012 and 2013 among men aged 50 to 74 years (15.7% to 16.5%; incidence ratio [IR] = 1.05; 99% CI, 0.96-1.15), or among men aged 75 years or older (65.8% to 66.4%; IR = 1.01; 99% CI, 0.91-1.12).

“We have to be cautious in the interpretation of the trend in distant-stage disease,” Jemal told HemOnc Today, “because 2 years is not long enough to know whether the disease is statistically significantly increasing or not. We have to monitor the trend for a longer time period.”

In a 2014 modeling study published in Cancer, Gulati and colleagues predicted that if PSA screening continued at its current rate, 710,000 to 1.1 million men would be overdiagnosed between 2013 and 2025, but that 36,000 to 57,000 prostate cancer deaths would be prevented during that period.

“That study showed that, if screenings really stopped in 2012 as recommended, it would double the number of men with metastatic disease by 2025,” Stacy Loeb, MD, MSc, urologic oncologist at NYU Langone Medical Center, told HemOnc Today. “It will be several more years before we can really examine those things, but the fact that fewer men are getting tested is concerning.”

Jim C. Hu, MD, MPH, professor of urologic oncology at Weill Cornell Medicine, is equally concerned. He coauthored a study — published in 2016 in JAMA Oncology — that used SEER collaborative staging analysis and produced results that appeared to contradict the findings from Jemal and colleagues.

Results showed the proportion of men aged 75 years or older diagnosed with distant metastasis increased from 6.6% in 2007 to 12% in 2013, and that the proportion of intermediate- and high-grade prostate cancers increased from 58.1% in 2007 to 72% in 2013 (P < .01). Among men aged 50 to 74 years, incidence of distant metastasis increased from 2.7% to 4%, and intermediate- to high-grade prostate cancer incidence increased from 46.3% to 56.4% (P < .01).

“It’s what most of us would have predicted, although somewhat sooner,” Hu said in a press release. “There was a decrease in prostate cancer metastasis and death after the advent of PSA testing. Remove the screening, and the rates of serious disease rise again.”

However, researchers and clinicians should “be very careful of those numbers,” Brawley said.

“They look at percentages of men diagnosed and not incidence rates of men diagnosed,” he said. “There’s an important distinction. We don’t know [the impact] yet. It is early for metastatic disease to increase because you would expect that to happen 6 to 8 years after screening decreased.”

Hu noted that, in his study, standardized incidence rates for men aged 75 years or older increased from 386.9 per 1 million men in 2011 to 434.7 per 1 million men in 2013 (P < .01). He maintains that improved biomarkers and imaging have limited the overdiagnosis and overtreatment of prostate cancer.

Brawley said he understands the concerns of urologists who believe a decline in testing may result in more metastatic disease.

“It’s a legitimate concern, and they could be right,” he said. “Because the number of men getting definitive treatment is going down, we may not be as good as we think we are in figuring out who should get definitive treatment.”

When evaluating the value of PSA testing, the flaws of the PLCO trial must be considered, Hu told HemOnc Today. In a letter to the editor published last year in The New England Journal of Medicine, Hu and Jonathan E. Shoag, MD, resident in urology at New York Presbyterian Hospital, contended the contamination rate of the control arm of the PLCO study actually approached 90%.

“People may view urologists finding flaws [in the PLCO trial] as trying to sustain their own cost of living,” Hu said. “That’s not the reason I do it. I’m doing it because I want to know the truth about whether we’re doing the right thing to get this annual test, [or] whether we’re overdiagnosing and overtreating men with prostate cancer, leading to undesirable side effects.”

An imperfect test

The FDA approved the PSA test in 1986 to monitor prostate cancer progression. Eight years later, the agency authorized its use — in conjunction with a digital rectal exam — to test asymptomatic men.

“PSA testing is a reasonable test, but it is far from perfect,” Penson said. “If it was perfect, this would be a very easy discussion because we’d have fewer false positives, fewer false negatives, and we’d be more targeted in our work-up. There’s no holy grail in prostate cancer screening, unfortunately, and that has become a problem.”

In addition to prostate cancer, a number of benign conditions can result in elevated PSA levels. These include prostatitis and benign prostatic hyperplasia.

“It’s not a cancer-detection test, it’s a test that detects abnormalities in the prostate,” Donald L. “Skip” Trump, MD, FACP, executive director of Inova Schar Cancer Institute and a HemOnc Today Editorial Board member, said in an interview. “Depending on how high the PSA is when it is first measured and found to be high, there’s anywhere from a 5% to 30% chance that it’s really cancer. Most men found to have an elevated PSA won’t have cancer. That’s because, as we get older and have intact gonadal function, our prostates enlarge. That causes the PSA to rise.”

Infection and inflammation in the prostate also increase PSA.

“It’s a great test to say there is something wrong with the prostate, but it’s by no means a cancer-specific test,” Trump said. “That characteristic, combined with the very high prevalence of prostate cancer, means there will be a lot of positive tests and a lot of cancer if you pursue that positive test. But some of those cancers didn’t need to be found, and that is where the real important conversations with patients have to occur.”

Part of the confusion lies in the Gleason grading system, which was updated in 2005 and again in 2014. Based on a Johns Hopkins study of more than 20,000 prostate cancer cases treated with radical prostatectomy and more than 5,000 cases treated by radiation therapy, WHO approved a new grading model that includes:

• Group 1 (Gleason scores less than 6) — only individual discrete well-formed glands;
• Group 2 (Gleason score 3 + 4 = 7) — predominantly well-formed glands with a lesser component of poorly-formed/fused/cribriform glands;
• Group 3 (Gleason score 4 + 3 = 7) — predominantly poorly formed/fused/cribriform glands with a lesser component of well-formed glands;
• Group 4 (Gleason score 8) — only poorly formed/fused/cribriform glands; or predominantly well-formed glands with a lesser component lacking glands; or predominantly lacking glands with a lesser component of well-formed glands; and
• Group 5 (Gleason scores 9-10) — lacks gland formation (or with necrosis) with or without poorly formed/fused/cribriform glands.

“Gleason 6 is a much less dangerous tumor today than Gleason 6 was just 6 years ago, because those elements got moved to 7,” Brawley said. “The fact that there are a lot more American men who are willing to be diagnosed and watched with Gleason 6 cancer means that the risk–benefit ratio is changing. Many men who have Gleason 6 disease are being watched instead of treated aggressively, whereas 10 years ago, they would have all been treated aggressively.”

Risk vs. reward

The harms of PSA testing include risk for fever, bleeding and infection from biopsy. Risks from subsequent surgery and radiotherapy for potentially indolent cancers include urinary incontinence, bowel dysfunction and erectile dysfunction.

During a prostate biopsy, a thin needle is inserted through the rectum, the urethra or the perineum, between the anus and scrotum.

A population-based study by Gershman and colleagues, published in 2016 in European Urology, showed prostate cancer biopsy rates fell 33% from 2005 to 2014. However, the proportion of men who experienced complications from biopsies increased from 14% to 18%, primarily due to nonsepsis infectious complications (P < .001).

In the ProtecT study, Hamdy and colleagues determined 31.8% of men who underwent prostate biopsy experienced grade 2 adverse events and 1.4% required hospital admission within 30 days.

“It’s rare, but bad things can happen when you stick a bunch of needles into the prostate,” Trump said.

There also are risks with treatment.

Radiation and radical prostatectomy, a procedure that removes the entire prostate gland along with surrounding tissue, are standard options for men with localized prostate cancer.

A salvage prostatectomy — performed if a patient does not respond to radiation — can be more challenging than radical prostatectomy due to scarring in and around the prostate. Complications from prostatectomies include incontinence, impotence and infection.

It’s imperative that urologists inform patients — especially those diagnosed with low-grade disease — of the risks involved with radical prostatectomies, Penson said.

“The world is changing, if for no other reason than patients know the side effects of treatments,” Penson said. “If you talk to a 60-year-old fellow who has a terrific sex life and you tell him he has a low-grade prostate cancer that is almost the same as an age spot, but to cure him means there is a good possibility his sex life is over and he will have urinary problems ... nowadays, patients hear that and say, ‘I like my sex life, I like being active. I’m willing to watch and wait.’ The needle is moving, and it’s a good thing.”

The bad thing, Trump said, is the “mindless conclusion” that prostate cancer detection must result in treatment.

“With radical prostatectomy, there is a very small — but not zero — risk for death, and incontinence and impotence are potential consequences of both radiation and surgical treatment of the disease,” he said. “There’s no doubt we sometimes treat cancers that do not need to be treated.”

That trend appears to be shifting, as more men opt for active surveillance.

A study by Cooperberg and Carroll, published in 2015 in JAMA, showed the proportion of men aged 75 years or older who chose active surveillance nearly tripled from the period between 2000 and 2004 (21.9%) to the period between 2010 and 2013 (76.2%).

Loeb and colleagues used data from the National Prostate Cancer Register of Sweden to show use of active surveillance there is even greater. They determined 91% of men diagnosed with very low-risk prostate cancer and 74% diagnosed with low-risk disease nationwide chose active surveillance in 2014.

“For years we overtreated prostate cancer because doctors knew that if they took out the prostate, their patient likely wouldn’t die of prostate cancer,” Penson said. “Now, patient and doctor awareness has moved to a different place. Prostate cancer care in the United States is probably not that much different than in Europe. But the United States has been a little slow to pick up on [active surveillance] because, culturally, we’re different. Americans hear the word ‘cancer’ and freak out. In 4 or 5 years, there may be similar usage of active surveillance in the U.S. and Europe.”

Unlike the previous concept of “watchful waiting,” when clinicians waited until patients reported symptoms before treating low-risk prostate cancer, active surveillance calls for PSA screenings and digital rectal exams every 6 months, along with periodic prostate biopsies. If aggressive growth is not observed, the interval between biopsies can be extended.

“There’s a little bit of gray area in terms of the guidelines of how frequently those tests should be performed,” Hu said, “but as our understanding of the indolent nature of a lot of these low-volume, low-grade cancers improves, we are backing off on the frequency of the monitoring tests.”

Incidence in black men

Black men are 1.8 times more likely to be diagnosed with prostate cancer than white men and 2.4 times more likely to die of it.

Despite these statistics, black men are “sailing in completely uncharted waters” because of limited study data from this population, Penson said.

The PLCO study helped influence the USPSTF recommendation against PSA screenings for all men, but only 4% of participants were black.

“They are minimally represented in randomized trials of screening, and they have a higher risk for aggressive cancer,” Loeb said. “That was one of the points the American Urological Association made in its response to the USPSTF recommendation. They thought it was concerning to make a blanket statement against screening when there is insufficient evidence, particularly for some of these higher-risk populations. My concern is that reduced screenings could further increase health disparities if black men are not being told about the test.”

The ACS recommends offering screening for men aged 45 years or older at high risk for prostate cancer, including black men who have a first-degree relative diagnosed with prostate cancer before the age of 65 years.

Black men are three times more likely than white men to have advanced, aggressive prostate cancer, according to a study published in 2013 in Journal of Clinical Oncology. Further, black men tend to present with high-grade cancers at the top of the prostate — farthest from the rectum — making them increasingly difficult to detect.

“I have been researching this for 8 years, and what my work has shown is that the tumors [of black and white men] are biologically different,” study coauthor Edward M. Schaeffer, MD, PhD, department chair of urology and professor of urology at Northwestern University Feinberg School of Medicine, told HemOnc Today. “Everything we know about PSA has been calibrated and established in Caucasians. Why hasn’t anybody done any calibration studies in African Americans?”

Schaeffer said his research shows “bad genes for prostate cancer” can be traced to West Africa. He received funding to study prostate cancer incidence in black men and hopes that, with continued development of genetic testing, targeted treatments can be developed for men of African descent.

Brawley said he is certain blacks have higher prostate cancer incidence and mortality rates than whites, but added he is not sure whether the disparity is driven more by environmental or genetic factors.

“I hate genetics of race arguments, but there are some studies that show blacks in Jamaica have more incidences than whites in Jamaica,” Brawley said. “We don’t have a lot of answers, but we need to do more genetic studies.”

Loeb said genomic tests — such as Prolaris (Myriad Genetics), Oncotype DX (Genomic Health) and Decipher (GenomeDx) — can provide more information on the biologic behavior of tumors, but these tests are just the “tip of the iceberg” when it comes to personalized medicine.

Overall, oncologic urologists agree discussions between physicians and patients about the benefits and risks of PSA screenings must happen more often.

“I go to my primary doctor every year, and he does not ask me if I want to have a PSA test,” Jemal said. “There needs to be a discussion.”

The importance of these conversations likely will be a primary focus of the USPSTF’s next recommendation, which could be finalized within the next 2 years, Penson said.

“I am hopeful [the task force is] going to reconsider its recommendation, because there has been a big change in the way prostate cancer is treated in the United States,” Penson said. “In 2012, the task force did not have a urologist and they did not really seek the input of urologists. Had they, any urologist would have said, ‘We’re seeing a lot more active surveillance. We’re seeing a lot more patients with low-risk disease not getting aggressive therapies.’ Now the data are showing that conclusively.” – by Chuck Gormley

Click here to read the , “Is genetic testing sophisticated enough to make PSA screening viable for mainstream use?”

References:

Andriole GL, et al. N Engl J Med. 2009;doi:10.1056/NEJMoa0810696.

Andriole GL, et al. J Natl Cancer Inst. 2009;doi:10.1093/jnci/djr500.

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For more information:

Otis W. Brawley, MD, MACP, can be reached at otis.brawley@cancer.org.

Jim C. Hu, MD, MPH, can be reached at jch9011@med.cornell.edu.

Ahmedin Jemal, DVM, PhD, can be reached at ahmedin.jemal@cancer.org.

Stacy Loeb, MD, MSc, can be reached at stacyloeb@gmail.com.

David F. Penson, MD, MPH, can be reached at david.penson@vanderbilt.edu.

Edward M. Schaeffer, MD, PhD, can be reached at edward.schaeffer@nm.org.

Donald L. “Skip” Trump, MD, FACP, can be reached at donald.trump@inova.org.

Disclosure: Brawley, Hu, Jemal, Loeb, Penson, Schaeffer and Trump report no relevant financial disclosures.