Right role for PSA screening difficult to define

Experts weigh the balance between excessive screening and aggressive treatment.

Depending on whom one asks, PSA screening is a waste of time for most men or a useful prognostic tool that saves lives.

The ACS, the National Comprehensive Cancer Network (NCCN) and the American Urological Association all take positions on PSA screening that could be described as a “cautious endorsement.”

The US Preventive Services Task Force (USPSTF) is less supportive than those organizations and was set to vote on new recommendations for PSA screening in November, but that meeting was canceled at the last minute. The agency was expected to recommend against PSA screening for men of any age, bringing the advice into line with recommendations issued in 2008 for men aged at least 75 years. According to the current guidelines, the evidence is insufficient to recommend for or against PSA screening in men younger than 75 years.

Some reports have suggested that task force members feared another backlash similar to what happened when the agency recommended against routine screening for women aged 40 to 49 years in 2009.

HemOnc Today talked to experts in the field to get their take on the proper role for PSA screening. There was little consensus on the benefit of screening, but physicians on both sides of the issue agreed on the need to separate diagnosis from treatment.

Otis W. Brawley, MD, chief medical officer and executive vice president of the American Cancer Society, does not recommend routine PSA screening. Photo courtesy of The American Cancer Society

Current USPTF guidelines said evidence is “insufficient to assess the balance of benefits and harms of screening for prostate cancer in men younger than age 75” and recommended against screening for men aged older than 75 years. The task force concluded that there is convincing evidence that PSA testing could detect some cases of prostate cancer, but determined that there is “inadequate evidence” showing that treatment for cancers detected by screening improved outcomes compared with treatment for cancers discovered by clinical detection.

“I don’t think that the scientific evidence supports PSA screening for any group of men,” said Michael J. Guarino, MD, a partner with Medical Oncology Hematology Consultants at Christiana Care’s Helen F. Graham Cancer Center in Delaware. “There may be a subset of patients who benefit; we just don’t know it yet.”

Otis W. Brawley, MD, has argued against PSA screening for 20 years and by virtue of his position as chief medical officer of the ACS, he is one of the screen’s most prominent critics. ACS does not recommend routine screening for all men, but said men who are of average risk for prostate cancer should discuss screening with their physician starting at age 50 years. Men at higher risk, such as blacks or men with a first-degree relative diagnosed with the disease, should begin the discussion at age 45 years, or even 40 years if those first-degree relatives were diagnosed before age 65 years.

“The ACS, the American Urological Association, the European Association of Urology and the NCCN have it right,” Brawley said. “What a man should know is not whether he should or should not be screened, he should know that there is a controversy. A guess needs to be made and who better to make the guess than an educated patient who is going to have to deal with the results of that guess?”

Brawley has written that the evidence supporting PSA screening is weak or nonexistent. He, along with Peter Boyle, MD, published an editorial in CA: A Cancer Journal for Clinicians in June 2009 that said, “For nearly 2 decades, testing has been based on blind faith in early detection as opposed to based on evidence of a decrease in mortality as observed in well-designed clinical trials.”

H. Ballentine Carter, MD, professor of urology and oncology at Johns Hopkins Medicine and director of adult urology at the James Buchanan Brady Urological Institute, however, said there are tangible survival benefits associated with PSA screening, especially for men aged 50 to 69 years, and rejects Brawley’s position.

“It’s a good test and it saves lives,” Carter said. “We probably need to do a better job of using it and focusing our screening efforts on populations for whom the test is beneficial.

“With all due respect to Dr. Brawley, he’s making an argument that I don’t think is supported by the randomized trials, excluding the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, which really doesn’t address the question because there was so much pre-screening already in the United States,” he said.

Michael J. Guarino

ERSPC vs. PLCO

Physicians had hoped that two prominent studies, the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the PLCO Cancer Screening Trial, would help settle the debate, but the results appear to have only confused the issue. ERSPC results showed a 20% relative reduction in disease-specific mortality after 9 years in men who underwent PSA screening without digital rectal exam. Researchers found no mortality benefit associated with PSA screening in the PLCO study.

The cohort for the ERSPC study included 19,911 men from Gothenburg, Sweden, born from Jan. 1, 1930, to Dec. 13, 1944. About 50% of the men were randomly invited to participate in screening, of which 7,510 accepted. After an initial PSA test, men younger than age 70 years who were not diagnosed with cancer were invited for up to six additional biennial screens.

“In unscreened men with PSA≥3 ng/mL, the risk of cancer rises in parallel with increases in PSA > 3 ng/mL; for men with prior PSA screens, the relation between a PSA elevation > 3 ng/mL and the risk of cancer essentially is flat,” Vickers and colleagues wrote in their study. “In other words, there was no significant relation between PSA and cancer risk in men with recent PSA screening and with a subsequently elevated PSA.”

Instead, the researchers found that a panel of four kallikrein markers (total PSA, free PSA, intact PSA and human kallikrein-related peptidase 2) was more predictive of biopsy outcome in men with elevated PSA levels than PSA alone.

Results from PLCO showed no difference in mortality in men who received PSA screening and those who underwent the usual care. In that study, researchers randomly assigned 38,343 American men to annual screening. Men in this group were offered annual PSA testing for 6 years and digital rectal examination for 4 years. Another 38,350 men were assigned to usual care as a control group. The compliance rate was 85% for PSA testing and 86% for digital rectal examination.

After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 in the screening group vs. 95 in the control group (RR=1.22; 95% CI, 1.16-1.29). The incidence of death per 10,000 person-years was two in the screening group and 1.7 in the control group (RR=1.13; 95% CI, 0.75-1.70). The data at 10 years were 67% complete and consistent with these overall findings.

There were 2,820 prostate cancers diagnosed in the screening group at 7 years compared with 2,322 in the control group (RR=1.22; 95% 1.16-1.29). The difference persisted at 10 years, 3,452 vs. 2,974 participants (RR=1.17; 95% CI, 1.11-1.22).

However, the increase in diagnoses did not result in an increase in OS, and in fact, OS was poorer in the screened group. At 10 years, 92 patients in the screening group had died compared with 82 in the control group (RR=1.11; 95% CI, 0.83-1.5).

“Screening was associated with no reduction in prostate-cancer mortality during the first 7 years of the trial, with similar results through 10 years, at which time 67% of the data were complete,” Andriole and colleagues concluded. “Risks incurred by screening, diagnosis and resulting treatment of prostate cancer are both substantial and well documented in the literature. To the extent that over-diagnosis occurs with prostate-cancer screening, many of these risks occur in men in whom prostate cancer would not have been detected in their lifetime had it not been for screening.”

A companion analysis by Schröder and colleagues showed that there was a prostate cancer incidence rate of 8.2% in the screening group compared with 4.8% in the control group, for a 0.71 absolute risk difference for death. However, researchers estimated that the rate of over-diagnosis was as high as 50%.

H. Ballentine Carter

Opposing viewpoints

There are, of course, supporters and detractors for both studies. In an editorial published in CA: A Cancer Journal for Clinicians, Brawley said the ERSPC results do more than show that PSA level was a poor predictor for prostate cancer. Instead, according to Brawley, these results showed that PSA screening can harm the men it purports to save: “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.”

Guarino said the ERSPC results only showed improvement in prostate cancer-specific survival, and any claims that screening saves lives based on this study are unsubstantiated.

“We are not smart enough to know what subset of men to screen with PSA, and in the absence of that knowledge, I’m concerned that we are hurting as many as we are helping,” he said. “We do not have clear evidence that we are saving lives, so we should not routinely be doing PSA screening.

“As a general rule for health care, we would better off spending the time counseling them not to smoke and to get to their ideal body weight because we know those things improve survival. It’s not clear that PSA [screening] improves survival,” Guarino said.

However, William J. Catalona, MD, said in a letter published in The New England Journal of Medicine that the PSA cutoff of 4 ng/mL used in the PLCO trial was outdated, and results were released prematurely. In an interview with HemOnc Today, he went on to refute the criticisms from Brawley and Guarino, noting that PSA-based screening, coupled with high quality treatment of appropriate patients, would be shown to improve OS over time.

Catalona, medical director of the Urological Research Foundation and professor of urology at Northwestern University’s Feinberg School of Medicine, pointed to results published in 2010 in Lancet Oncology from a prospective, population-based study of disease-specific mortality after PSA screening undertaken with nearly 20,000 men in Göteborg, Sweden. Patients in the study were aged 50 to 64 years and the PSA threshold required for men to continue on to further examination ranged from 3.4 ng/mL to 2.5 ng/mL during the course of the study.

Those results showed that PSA reduced prostate cancer-specific mortality by 44% (95% CI, 0.17-0.64) in the screening group at 14 years (56% in men actually screened), and that only 12 men had to be diagnosed to prevent one prostate cancer death. Not all were treated; many were mangaged with active surveillance.

Catalona reviewed the study and called it “the best prospective prostate cancer screening trial reported to date” because it was population-based, better conceived and executed, and included a longer follow-up time than either the PLCO or ERSPC trials.

However, even these results are a bit ambiguous because researchers said “the risk of over-diagnosis is substantial and the number needed to treat is at least as high as in breast cancer screening.” But they added that the benefits of PSA screening “compares favorably to other screening programs.”

In a review of current ACS guidelines published in January by CA: A Cancer Journal for Clinicians, the researchers, including Brawley, said the “significantly smaller number” of men who needed to be diagnosed to save one life observed in Göteborg was “consistent with the expectation that with additional years of follow-up, these numbers would become more favorable.

“However, similar to ERSPC, this study found that the majority of the mortality benefit achieved through screening occurs after 10 years, leading the authors to emphasize that policymakers should be cautious about promoting screening for all elderly men,” the researchers wrote. “In addition, and very importantly, at 14 years of follow-up, the control and screened groups had the exact same overall mortality.”

William J. Catalona

Uncouple diagnosis from treatment

The experts who spoke to HemOnc Today have strong and opposing opinions on PSA screening. Guarino said he does not believe that screening has any utility and tells his patients that there is no evidence that screening will save their lives, and he discourages them from going through with the test. Brawley said the screen has minimal value at best, and even that is outweighed by the risks posed by over-diagnosis.

Carter, however, said he is unwavering in his belief that screening saves lives. Catalona was the first physician to use PSA screening to find cancers and said 20 years of anti-PSA propaganda has turned some of the public and primary care physicians away from a valuable resource.

However, all agreed that physicians and the general public should stop believing that treatment must inevitably follow a diagnosis of prostate cancer.

“The problem is that, in our country, diagnosis and treatment are so closely coupled as compared to Europe,” Carter said. “That, in my opinion, is the essence of the controversy.”

Most prostate cancers are slow-moving and, especially in elderly men, are unlikely to cause death. According to current guidelines, men with “less than 10 years of life expectancy” should consider active surveillance instead of treatment, but Guarino said there are still too many men getting unnecessary screens, especially the elderly, and unnecessary treatment.

Carter and Brawley said it would take a program to educate both the public and physicians about treatment options. Public opinion changes slowly, however, and physicians have a strong financial incentive to order treatment whether it is necessary or not.

“It’s not going to be a physician-led grassroots effort,” Carter said. “It’s going to take the public saying, ‘Wait, is this necessary?’”

Catalona, though, said more men should be getting PSA exams.

“All of the media’s anti-PSA articles have had a negative effect on PSA screening. In the past 2 or 3 years, fewer men are getting tested. I’m seeing men in my practice who have had a hiatus in their PSA testing. When they came back, they discovered they’d had a big jump in their PSA level,” he said. “The people out there who are against PSA testing and who are sending out the message that men should not be tested and that they should not be diagnosed with prostate cancer are doing a disservice and misleading people.”

The rate of PSA screening decreased, but only slightly, after publication of the ERSRC and PLCO studies, according to results of a review published online in Journal of the National Cancer Institute in February. PSA testing decreased among men aged 40 to 54 years (3%), 55 to 74 years (2.7%) and older than 75 years (2.2%). However, Zeliadt and colleagues concluded that the decrease was not significant in the 55 to 74 years age group.

Researchers said PSA testing among men older than 75 years initially declined slightly after the 2008 USPSTF recommendations against PSA testing for men older than 75 years and continued to decline after the trial results were published.

But even Catalona said the problem was too much treatment, not too much screening, adding that screening is necessary to give the patient a full range of options.

“You don’t have to link diagnosis with treatment. If patients have an honest and sincere doctor who is going to do what is best for the patient, there will be people who are diagnosed who don’t need to be treated aggressively,” he said. “But, if you don’t do the PSA testing and you don’t diagnose the cancer, the patient will not have the opportunity to be treated.” – by Jason Harris

For more information:

• Andriole GL. Cancer. 2011;117:1110-1112.
• Andriole GL. N Engl J Med. 2009;360:1310-1319.
• Barry MJ. N Engl J Med. 2009;360:1351-1354.
• Boyle P. CA Cancer J Clin. 2009;59:220-224.
• Brawley OW. CA Cancer J Clin. 2009;59:264-273.
• Carroll PR. J Clin Oncol. 2011;29:345-354.
• Esserman L. JAMA. 2009;302:1685-1692.
• Greene KL. J Urol. 2009;182:2232-2241.
• Hugosson J. Lancet Oncol. 2010;11:725-732.
• Kolata G. Cancer society, in shift, has concerns on screenings. New York Times [online]. Oct. 20, 2009. Available at: www.nytimes.com/2009/10/21/health/21cancer.html. Accessed March 8, 2011.
• Lilja H. Cancer. 2010;117:1210-1219.
• Neal DE. Lancet Oncol. 2010;11:702-703.
• Schröder FH. N Engl J Med. 2009;360:1320-1328.
• Smith RA. CA Cancer J Clin. 2011;61:8-30.
• US Preventive Services Task Force. Ann Intern Med. 2008;149:185-191.
• Van Leeuwen PJ. Cancer. 2010;116:4857-4865.
• Vickers AJ. Cancer. 2010;116:2612-2620.
• Zeliadt SB. J Natl Cancer Inst. 2011;103:520-523.

Disclosures: Drs. Brawley, Carter and Guarino reported no relevant financial disclosures. Dr. Catalona reported a financial interest in PSA test manufacturers Beckman Coulter, Nanosphere and Ohmx.

.

Are too many men undergoing PSA screening?

We not only need less testing, but also more intelligent testing.

It’s not just too many men are being screened, but also too many men are repeatedly being screened. What we’re seeing now is not only a higher penetrance of screening but also a lot of very intense screening and what I call re-screening — many PSAs, many digital rectal examinations, many biopsies.

Peter R. Carroll

What we need is more intelligent testing. That means perhaps screen earlier, developing a better understanding of a man’s future risk for prostate cancer, using more than just PSA alone to determine the need for biopsy and screening at appropriate intervals based on initial PSA. Some men may be screened more frequently, some may be screened less frequently and there is increasing evidence that there are some men we can stop testing altogether.

We can’t incorporate this into the guidelines yet, but in the near future, we’ll be able to recommend discontinuing screening for men aged in their mid-60s based on PSA level. What we’ll do is start screening earlier, start screening better and we’ll stop screening at a certain point.

Right now, a lot of screening is based on a PSA cut point, and unfortunately, that PSA cut point is going down. We’re doing more biopsies at lower PSA levels, we’re doing more extended pattern biopsies. We’re using things that may not be very predictive, such as PSA velocity. We’re doing an awful lot of screening that is probably neither effective nor efficient.

Peter R. Carroll, MD, MPH, holds the Ken and Donna Derr — Chevron Distinguished Professorship in Prostate Cancer and is the associate dean of the University of California at San Francisco School of Medicine.

Disclosure: Dr. Carroll reported no relevant financial disclosures.

By and large, the overwhelming majority of patients are appropriately screened.

For men aged between 50 and 69 years, by no means are all of those men getting screened. There will be variations by market and individual physician, and there are large numbers of physicians who strongly feel that screening is inappropriate, so their patients are going to be screened rarely, if at all.

There’s also a group who get screened because, for the busy clinician, it’s often easier for him or her to screen than to think through which patients should be appropriately screened. That’s unfortunate, but it’s the reality of health care in our country today.

J. Stephen Jones

The American Urological Association recommends a single screen starting at age 40 years and the guidelines become less clear after that point. In my own practice, if a 40-year-old patient has an unusually good PSA, less than 1.0, he probably doesn’t need to be screened for another 5 or 10 years. If his PSA is above 1.0 at that young age, by no means does he need a biopsy, but he certainly merits annual screening because those are the patients who have been shown to be at significant risk for developing clinically significant cancer in the future.

What we need are reasonable guidelines for people who are taking care of patients every day. Many times, these recommendations are developed by people who sit around conference rooms only thinking about one issue at a time. The reality is primary care physicians have to deal with a lot of things on a regular basis all day long and into the evening.

We used to debate whether screening reduced the likelihood of dying from prostate cancer. It’s now been firmly established that we can reduce the risk for dying early from prostate cancer by screening, but we have to ask, at what cost to the individual patient? Lots of patients are going to get treated to save some small number from dying.

J. Stephen Jones, MD, is chairman of the department of regional urology of the Glickman Urological and Kidney Institute at Cleveland Clinic.

Disclosure: Dr. Jones reported a financial relationship with EndoCare.