By Mark Wolf

Dr. Edward Eigner had been talking about the controversy regarding prostate-specific antigen (PSA) tests and prostate cancer for about 10 minutes when he slid his chair back, strode out into the hallway and returned to his office carrying a  sheet of paper encased in a plastic sleeve.

On one side is a graph from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute showing prostate cancer incidence from 1992-2007. After a bulge in the first two years, the graph’s line is relatively flat.

“Why is it higher (in the beginning)? Because PSA was introduced back here and so there’s a whole bunch of (men) out in the community who had an elevated PSA but had never been screened. For the first couple of years everyone who walked in had an elevated PSA, so you had a big jump at the beginning,” said Eigner, a urologist and surgeon at Urology Associates, which has three locations in metro Denver.

Dr. Edward Eigner

“Then over time the true incidence of the disease is recognized and it flattens out. We’ve improved our techniques, but our treatment hasn’t changed. We still take out prostates and radiate prostates. Our treatment hasn’t changed, but look what’s happened to the death rate.”

Eigner flips the sheet over to reveal a chart of prostate cancer mortality during the same years. The line representing deaths from the disease declines steadily from nearly 40 per 100,000 population in 1992 to about 25 in 2007.

“So someone has to give me a rational explanation why if we haven’t changed treatment and the same number of people get prostate cancer, how come so many fewer patients are dying. That’s even more pronounced in an era when people are living longer and longer and they have longer to die of prostate cancer.”

His answer is that the PSA test is catching prostate cancer at an early, treatable stage.

Last October the U.S. Preventive Services Task Force recommended that healthy men no longer be screened for prostate cancer using the PSA test because the test does not save lives overall and often leads to more tests and treatments that needlessly cause pain, impotence and incontinence in many.

Dr. Virginia Moyer, pediatrics professor at the Baylor College of Medicine and chair of the task force, disputes the conclusion that PSA testing is responsible for the decline in prostate cancer deaths.

“If you look at the timing of the fall in prostate cancer deaths, the fall predated the time when the PSA could have been the cause of that fall. The fall actually began about the time PSA screening started, but PSA screening can’t benefit until about 10 years out. It takes that long for the benefit to show for the screening test,” she said.

“Why (the mortality rate is falling) is not completely clear. Overall, our treatment has probably become much better; we’re probably doing a better job of treating the cancers that do present. That doesn’t totally explain the decrease, but it certainly means you can’t look at the 40 percent decrease just because it’s at the same time as PSA screening.”

Dr. Virginia Moyer

The task force did not recommend that patients should never have PSA tests — “There are many good uses for it,” said Moyer — only that men without symptoms should not be routinely offered a PSA screening.

“If I were a treating physician what that would mean is I wouldn’t bring it up because it’s not something that needs a lot of time if the patient is not concerned about it. If the patient comes in and says ‘Do I need a PSA test?’ then you have to have that conversation about the pluses and minuses, but there’s certainly no place for ‘I refuse to do this,’ ” said Moyer.

“It is probably true that some small proportion of men may benefit and many more will be harmed. When you’re in that position as a physician and someone asks for something, that’s a discussion you need to have, but you don’t bring it up,” she said.

The task force reported that for every 1,000 men treated, five will die from complications of surgery, between 10 and 70 will have serious complications but survive, and 200 to 300 will develop urinary incontinence, impotence or both.

Eigner said he was disappointed with the task force’s recommendation.

“The implication is that if you have an abnormal PSA, that triggers a biopsy which triggers a prostatectomy and we don’t have evidence that it prolongs life. In fact I spend my entire day discussing the complexities of that test and how we should use it and how we shouldn’t, often repeating it and repeating it over years in serial fashion and using it in combination with prostate size and family history and with risk factors, biopsy history and then come up with a conclusion of whether it’s worth doing a biopsy and then taking any further steps.

“All of that interpretation part has been ignored by the commission and I think they’ve made a huge error because people look at headlines,” said Eigner. “How do you expect them not to?”

Issue often is personal

Dr. Stuart Holden, a specialist in urological cancer, is the director of the Louis Warschaw Prostate Center at Cedars-Sinai Medical Center and medical director of the Prostate Cancer Foundation.

“On a practical basis for someone like me who takes care of prostate cancer patients, the people who make those recommendations do it from a public health point of view, but they don’t sit in a room with a patient who says, ‘My father or my best friend just died of prostate cancer. It was a horrible way to die.  I watched it and don’t want to go through it. What do you think I should do?’ The first thing I think you should do is have a PSA.”

Holden said that an elevated PSA is a sign of one of three things or a combination: an enlarged prostate, an infection in their prostate or prostate cancer.

Dr. Stuart Holden

“It wasn’t designed for this particular use, but for a test that’s not very good, it’s had a pretty hefty positive impact and it’s also had a pretty significant negative impact,” he said.

“Everybody understands the limitations of PSA. It’s not a specific tumor marker; it creates a lot of clinically difficult questions; it’s not precise; it’s not specific; and it’s not 100 percent reproducible. Having said all that, it was never meant to be the end all and be all of prostate cancer,” said Holden. “If you look at the outcome of the so-called PSA era in prostate cancer detection and treatment, several things become apparent.”

In the days prior to PSA tests, Holden said a large number of men with prostate cancer weren’t diagnosed until the disease had spread beyond the prostate and was by definition incurable.

“That rarely happens today. That’s a huge change,” he said. “For those of us who were around then, the whole profile of the patients you see is completely different.”

it’s also true that PSA has led to over-diagnosis, he said. “Many unnecessary prostatectomies have been done; everybody agrees on that. It’s not a revelation to anybody who works in the field.”

Holden said that our medical system probably spends too  much money on the test and too much  over-treating as many as half the people diagnosed with localized prostate cancer.

“At the present time we can’t always detect who’s being over-treated and who’s being treated appropriately until after the fact.”

Patients with abnormal PSA results or low-grade cancers are increasingly referred to “active surveillance” during which their condition is monitored with additional testing and/or repeat biopsies.

“I’m a huge proponent of active surveillance,” said Eigner, who has dozens of patients on surveillance protocols. “In the old days it used to be more difficult to talk them into it. They hear the word ‘cancer’ and they want it out yesterday. But now when I make a new diagnosis, I call them and explain what it is, say, ‘Here’s the shorthand but get this book, go to this website.’ ”

Holden said attitudes about surveillance are cultural.

“In Scandinavia a high percentage of people offered the option of waiting on treatment will take it, where in this country very few people up until now do. That’s starting to change and that’s where the press can be helpful,” he said.

The inability of the medical establishment to give men better guidance about prostate testing is frustrating to many.

“Doctors argue and patients fret,” said Dr. Thomas Flaig, a medical oncologist who is an associate professor and medical director of the Clinical Investigations Shared Resource at the University of Colorado Cancer Center.

“It drives me nuts that we can’t as a group make some more definitive ‘this or that’ and agree. As tough as it is for me to dance around the pros and cons of this, the poor patients are stuck with unclear guidance on a complex topic.”

Flaig said he didn’t agree with the starkness of the task force’s recommendation that men not be screened for prostate cancer. “The hard core evidence to support prostate cancer screening is not terribly strong. An informed man who chooses to undergo screening should be able to do that and it should be covered by insurance. However, I also think routine, not-informed screening does not make sense.”

Not like other cancers

Prostate cancer is not like other cancers.

Dr. Thomas Flaig

“Most men get it if they live long enough. That’s not true of other cancers,” said Flaig. “It’s not a question of finding it. We’re really good at that. The challenge is that the majority of 65-year-old men, certainly 85-year-old men have it. The problem is determining which one is a mortal threat and which one is not.

“We don’t have perfect tools to differentiate so we compensate by treating a large number of men who won’t necessarily need therapy, so we don’t miss one potentially lethal cancer. Three percent of the men die from it when the majority of men are going to get it so there’s a huge disconnect. Most men die with it; 3 percent die from it.”

The men who may be saved by early detection are cited by urologists as a compelling argument for widespread screening.

“The question really becomes, you have to do 20 surgeries to save one life or you have to do 46 biopsies to find one cancer. If you’re that one, what’s it worth? Who’s going to decide those questions?” said Holden.

Moyer answers the question with a question: “How do you know that patient would have died? Ninety-five percent of them would have died without knowing they had prostate cancer so how do you know if this particular patient was in the small proportion who might have benefited from testing?

“For any one individual we have this picture that if you have cancer in you that it will grow until it kills you. That is simply not the case,” said Moyer. “It is not the case with prostate cancer, probably the case with many if not most cancers.”

Moyer said that a significant proportion of prostate cancers, depending on what type of cancer they are,  either do not progress, do not progress fast enough to manifest itself before you die of something else or, amazingly, sometimes  just go away.

“The fact that your cancer was found and you had your cancer removed and you are now alive, that’s true, true, true and potentially unrelated,” Moyer said. “For some people that is true. The number of people for whom that is true is very, very small. The number of people who are harmed by the intervention is not small and what we looked at is the balance of benefits and harms.

“The problem is if the person who benefits and the person who is harmed is the same person, that would be a thing for a person to say, ‘OK, I’m willing to take this risk.’ The problem is, it’s not always the same person.

“What do you say to the guy who had a non-aggressive cancer and who dies of a pulmonary embolism post-op. Five out of 1,000 die within a month. They’ve not only not gotten the benefit, they’ve gotten the ultimate harm and they’re paying for the guys who benefit,” said Moyer. “We need to not forget about those guys.”

Flaig said the psychological impact of being diagnosed with cancer needs to be considered as well.

“We focus mostly on the financial costs of this or the side-effects or the loss of sexual function, but there’s also the cost of psychological burden of knowing, ‘I’ve got cancer.’ For many people that will change their lives and that’s very difficult to quantify.

“Once the big C word falls out of the sky and they’ve got cancer, they will look at their lives differently a good percentage of the time. How am I going to make this decision? How am I going to plan my retirement, how am I going to plan my savings, my family time, my insurance? What is this going to do to my health insurance?

“Many of the men who are diagnosed have a quote/unquote ‘insignificant’ or ‘low risk’ prostate cancer. This situation is going to be hardest for them. It wouldn’t necessarily make sense based on our current prognostic tests to be treated, and so there are things such as active surveillance or deferred treatment, but the psychological burden of knowing they have cancer is life-long. I think that’s a harm that’s been under-appreciated over time,” Flaig said.

The dread of cancer can prompt men to opt for treatment even for low-risk cancers.

“I can say, ‘You have a low-risk cancer. It’s low-grade; your PSA is low and there’s not a fast trajectory upwards. I would recommend considering active surveillance,’’ said Flaig. “But patients often still want to pursue active treatment.

“I’d say, ‘I think you’re going to survive this either way.’  I can say the odds are very high this will not be a threat to you. Oftentimes they want to have it removed or radiated, even if the risk of progression is small.”

Better diagnostic tools needed

Everyone agrees on the need for more reliable diagnostic methods as well as a test that could predict which cancers are aggressive and which are not.

“The idea is to validate the test before we implement the next test into widespread use,” said Flaig. “Recently in the Journal of the National Cancer Institute, they published the long-term follow-up on the PLCO (Prostate, Lung, Colorectal and Ovarian) trial, which includes a large prostate cancer screening cohort: over 70,000 men who had prostate cancer.

“We’re now getting the 13-year follow-up to that, which shows no survival benefit to screening. The frustrating part is if we do have a new test that looks like gangbusters, how long is it going to take for us to validate the new test to prove that this does sort through those who have a mortal risk and those who have a cancer that is just along for the ride? That’s the challenge,” said Flaig.

“The next time we have a test that looks good we ought to validate it before we put it into general use. We didn’t do that with the PSA.”

The PLCO trial is not without its critics. Many doctors argue that the trial was seriously flawed because about half the men in the non-screening group ended up getting one or more PSA tests during the trial period, making it difficult to determine the real effect of screening.

Holden said the PCA3 genetic screening test is promising.

“It’s not perfect but what will happen is eventually there will be a multiplex test that will probably measure lots of different things in an algorithmic way, probably 8 or 10 or 15 biomarkers. It has been shown there are probably 23 varieties of prostate cancer, some of them aggressive, some of them not. We’re starting to learn how to categorize these molecularly as to whether they’re aggressive or not,” he said.

“In keeping with the whole general theme of personalized medicine, in the next few years we’re going to be able to take a hard look at this stuff and PSA will become a relatively much lesser player. It’s the only thing that’s out there right now, but PCA3 has worked its way into our practice and more than 10 companies are developing other things that look very interesting.

“The field is growing rapidly and I think this PSA thing will become somewhat academic.

Flaig is hoping for more consensus on testing guidelines.

“What I would like to see is that as physicians we come together across specialties and make some reasonable recommendations that we can all follow to guide our patients. The current conflicting recommendations are not a good service to our patients.

“Unfortunately I don’t see that as an imminent change. I see us becoming more polarized in our recommendations. The task force is a marker to the far side of saying do not screen and some patients could potentially lose the opportunity even if they choose to pursue. The other side of the coin is the saying the data are not good when starting at 50 years old, so try 40 or 45. If we get those competing recommendations from two legitimate medical groups out there, it puts patients in a quandary, so I hope we can come together in the next 10 years. It’s going to take some leadership from individual specialty groups that do that.”