PSA Testing in Prostate Cancer: Early Treatment vs Observation

H. Ballentine Carter, MD

Timothy J. Wilt, MD, MPH

Prostate cancer is the most common cancer in men in the United States and also the second leading cause of cancer death in the United States, according to the American Cancer Society. But many men are diagnosed early thanks to prostate-specific antigen (PSA) testing during regular physicals, and these cancers tend to be slower growing and non-aggressive. How to care for men with these early stage tumors-whether so-called watchful waiting is appropriate or whether surgery is the best option remains a major question. Recent results from several long-term studies that compare these methods show different results, but these studies looked at different types of patient populations, which does not always allow for direct comparisons.

To discuss this topic, we are joined by Timothy Wilt, MD, professor of medicine at the University of Minnesota School of Medicine and investigator at the Center for Chronic Disease Outcomes Research at the Department of Veterans Affairs, and H. Ballentine Carter, MD, professor of urology at Johns Hopkins University.

-Interviewed by Anna Azvolinsky, PhD

Cancer Network: Dr. Carter, could you describe the different approaches to early-stage diagnosis, watchful waiting and active surveillance vs active treatment? What are the factors to take into consideration when deciding which route to take with a  prostate cancer patient?

Dr. Carter: I would make the distinction between watchful waiting and active surveillance here. What is usually meant by watchful waiting is an approach that is generally appropriate for an elderly individual who is not necessarily fit to undergo curative intervention. For example, they have a 5-year life expectancy or less. In those individuals it makes sense, for many of them, to monitor their situation but not treat it aggressively unless the disease progresses and causes symptoms (eg, urinary obstruction or spread and metastatic disease).

That is very different from the term active surveillance, which is a term that has been used more extensively in the PSA era when we are detecting cancers on average 10 years earlier compared to the pre-PSA era. And this approach, called active surveillance, is an approach that is very different because it involves men who would be fit for curative intervention, so there is not the same limitation of life expectancy. The goal and the idea is to identify those individuals who are at low risk for being harmed by their cancer, monitor them very carefully (with period tests and PSA measurements and sometimes serial prostate biopsies) to find those men whose disease changes, and then intervene in a delayed way, for those whose disease has changed, using curative interventions, (eg, radiation therapy or surgery). So these are very different approaches and the idea with active surveillance is to try to reduce the overtreatment that is caused by screening.

I will emphasize that for active surveillance-but actually for any management option, whether its monitoring or curative intervention-the physician first has to assess the disease. What is the risk that the disease will actually cause harm? Whether it is an aggressive disease or not and that is usually done with a combination of the PSA test (the higher the PSA level the more aggressive the disease is in general) and the best predictor we have called Gleason scoring (the higher the grade the more aggressive the disease). All of these are used to determine appropriate management. The second thing that has to be considered is life expectancy. What are the remaining years of life for this individual based on their age and comorbidities? And the last thing, and perhaps most important, is the patient’s personal preference. Is this someone who can live with their cancer and is comfortable monitoring. Or is it someone who prefers to treat it even though there are risks of potential side effects?

Cancer Network: Dr. Wilt, you were the lead investigator of the US-based Prostate Cancer Intervention vs Observation Trial, which is also called the PIVOT study, that was published in the New England Journal of Medicine in 2012. Can you describe this study and the major findings?

Dr. Wilt: Sure I would be happy to. First I'll just say that I agree with a lot of what Dr. Carter mentioned, and PIVOT helps to address some of the comments he made, particularly on the role of watchful waiting and also the potential role of active surveillance. First let me describe the study, and then its results and how it might get back to the management of patients, particularly in the PSA-diagnosis era.

Similar to a more recent study published in the New England Journal, PIVOT was a randomized study that compared surgery to observation, or watchful waiting (not active surveillance), in over 700 men who had early-stage prostate cancer, a little more than half of them were detected by PSA testing. The goal of the study was to determine whether surgery improved the length and quality of life and reduced death from prostate cancer in these men. What we found after a follow-up that extended out to 12 years, was that compared to watchful waiting, surgery did not improve the length of life or prevent deaths from prostate cancer compared to watchful waiting in these men. The absolute difference between the two groups was less than 3%.

I think these are important findings and differ somewhat from this current study. This is particularly important in the era of PSA testing where men often have smaller volume, lower grade, lower risk tumors. What we did find in the PIVOT study, which I think is consistent with what the Scandinavian study showed, is that in some men, surgery did appear to have a benefit in terms of prolonging life and reducing death from prostate cancer. And in those men, surgery may indeed be beneficial. In particular, we found that those men with higher risk disease, as described by Dr. Carter, or those with PSA values above 10 had an improvement. But for the majority of men currently diagnosed with PSA testing, our study indicates that observation can be a wise, effective, and safe option, and results in a similar length of life, prevention of death from prostate cancer or spread of prostate cancer, and avoidance of the harms from surgery (especially the urinary incontinence and erectile dysfunction).

So just to clarify, I think what PIVOT and other studies suggest about the role of watchful waiting-and I agree that watchful waiting may not be the best option for some men, and maybe even many men, for the various reasons that Dr. Carter described-is that it can be a valuable treatment option for those men with a life expectancy of 10 and even 15 years (our study goes out 12 years) particularly in the PSA era. And again, it resulted in similar length of life, prevention of prostate cancer death, and avoidance of harms related to surgery. Active surveillance is a useful option that has many of the advantages that Dr. Carter described. It is currently being evaluated in a study over in the United Kingdom. The main concern I have with active surveillance is that it requires periodic biopsies that have harms-including pain, fever, and infection-that can be serious. And it may result in treatments that are unnecessary and potentially ineffective, and this requires additional study.

Cancer Network: The more recently published study that you alluded to, Dr. Wilt, from Sweden and researchers at the Harvard School of Public Health, showed that men under the age of 65 who had a radical prostatectomy were less likely to die from their prostate cancer compared to those who were observed. How is this study different than the PIVOT study in your mind, Dr. Carter?

Dr. Carter: Well, as Dr. Wilt alluded to, the Scandinavian study was done before the PSA era. So the individuals in this newer study were very different than those in the PIVOT trial. If you look at the people in the Scandinavian trial, only 5% of them had prostate cancer detected through screening. And they had disease that was further along than men in the PIVOT trial. For example, three-fourths of them had disease that could be felt on a rectal examination, one-third of them had higher grade disease, and almost half of them had PSA levels of 10 or more. You heard Dr. Wilt say that the individuals that benefited from surgery in the PIVOT trial were more likely to be those men who had PSA levels above 10. So, the point is that in the Scandinavian trial, many of these men were the people who were in the PIVOT trial who were shown to have some benefit or derive benefit from treatment. So I think they are very different trials, and it is hard to generalize from the Scandinavian trial what we are detecting today. But if I had to interpret the Scandinavian trial, I would say that the update that was published recently strongly suggests that if you are over 65 years of age and you get diagnosed today with a cancer that we consider to be at low risk of causing harm, then that person should be asking not which treatment is appropriate, but whether or not they even need to be treated.

Dr. Wilt: I would like to really agree with that point strongly. It expands the number of invidividuals who could be really reassured in a positive way, that they are unlikely to be bothered by their prostate cancer in their lifetime and can avoid the harms of early treatment that is not necessary. That is a positive thing we can tell our patients and arguably, one of the best things we can do is to not be looking so hard to find them. So in the era of PSA testing, it might be rather than lowering thresholds and frequency of testing, to instead raising thresholds of what we call abnormal and triggering a biopsy and maybe lengthening the interval of testing from every year to every 2 to 4 years. And this might help to reduce what we call overdiagnosis and that process, that cascade of events, that unfortunately leads to overtreatment.

Cancer Network: Are there other important studies that have provided evidence either for or against early treatment in the last few years or any that are ongoing now that either of you can highlight?

Dr. Wilt: Let me just again discuss that the results of this Scandinavian study are a continued follow-up that have been previously published. I think that they do add important, new information, up to 15 to 20 years for men that are diagnosed primarily by a digital rectal exam and not by PSA testing. As I earlier alluded to, there is a study ongoing in the United Kingdom called the PROTECT (Prostate Testing for Cancer and Treatment) study that is comparing surgery to active surveillance to external beam radiation therapy in men primarily detected by PSA testing. And those men will have smaller volume tumors and less aggressive tumors than even those in the PIVOT trials, so I think this will add valuable information. There have been a variety of lower-quality studies, what we call observational studies, where people get some treatment and we just watch them out, which suggest that watchful waiting or active surveillance may be a safe and effective approach for a large number of men who have their prostate cancer detected by PSA. Dr. Carter described who those men might be-men over 65, men with low-risk disease, low PSA.

And then finally, a study that has unfortunately has not seen publication but was presented at a meeting several years ago, compared external beam radiation therapy to watchful waiting, another Scandinavian study. And at this point, has shown no benefit through about 15 to 20 years of radiation compared to observation in overall survival or death from prostate cancer. Again, those patients were not in the PSA era but this calls into some question of the effectiveness of radiation therapy for many men.

Cancer Network: Dr. Carter, do you have anything to add?

Dr. Carter: I would like to just summarize and say that I could not agree more with Dr. Wilt. I think we have overdone PSA testing in this country and the downstream consequences of that have been overtreatment of prostate cancer. We need to do a much better job identifying those people who are actually going to benefit from treatment and not treating everyone the same way in this knee-jerk response where they get diagnosed with prostate cancer and need to be treated. I think we are headed in that direction, and certainly Dr. Wilt has been a strong advocate of this.

Dr. Wilt: Let me also echo this. Dr. Carter was the lead on the recent American Urological Association clinical practice guidelines on PSA testing and there have been others put out by the US Preventive Services Task Force, and the American College of Physicians groups that I have sat on. And I think what we are really seeing is groups coming together, looking at the information, recognizing that as you start off the programs that prostate cancer is common and potentially serious and deadly and that we need to do something to safely and effectively find those individuals and treat those that need it, because it is a major health problem. But we also have to be very aware that at least in the recent past-and I would argue, that even currently-of testing so many individuals and using low thresholds for biopsies and treating a lot of them, has resulted often in a balance of benefit that don’t always exceed the harms. We need to do better with that and there are ways to improve that balance such that we can safely and effectively treat men who need it and benefit from it, but avoid it in those who don’t.

Cancer Network: Lastly, what are both of your approaches and views on how to approach PSA screening? Dr. Carter let’s start with you.

Dr. Carter: So, Dr. Wilt mentioned the American Urological Association guidelines, which I helped put together, and I support those. I think that what we tried to emphasize was a more targeted approach to PSA testing. This means that for a man who is of average risk, not a high-risk individual, but a man who is at average risk for developing prostate cancer, it is reasonable to have a discussion with that individual when between the ages of 55 and 69 and let them know what the potential benefits are and the potential harms, and then after hearing that, make a shared decision about PSA screening. The American Urological Association does not recommend routine PSA screening for the average-risk individual under the age of 55 or over the age of 70. But I will emphasize again that the American Urological Association did not say that no man under age 55 or over 70 should be tested. We know that there are extremely healthy older men who may benefit, and there are obviously individuals who are at higher risk because of their race or a very strong family history, who could benefit from PSA screening at an earlier age. So just to summarize, our statements in the AUA guidelines were addressing the average risk, asymptomatic man. And I totally agree with what Dr. Wilt said, and what we also emphasize in the guideline, that if it’s determined that the individual wants to be screened, annual screening is probably unnecessary.

Dr. Wilt: I think that the AUA guidelines are really a strong step forward and I think that there is a lot of commonality with those guidelines and the guidelines that I mentioned where some of the differences are often highlighted with the wording. The US Preventive Services Task Force recommends against PSA screening and that is because the way they look at the information is that they recommend against screening tests where the benefits are felt not to exceed the harms. But patients often want a recommendation from their provider, ‘what do you recommend doctor?’ But similar to the AUA and other guidelines, if after informed discussion with the patient, the patient still desires screening, it is reasonable to order the test and as we have discussed here, just to try to mitigate against overdiagnosis and overtreatment. One reason why I think the American College of Physicians as well as the US Preventive Services Task Force has come out a little stronger against PSA screening is that evidence from the randomized trials show no benefit in men over age 70 and men under age 55, and it's rare in men under age 55. We understand that there may be some men who have exceptional life expectancy or are at higher risk, but the balance at the population level or even at the individual level is unclear at this time-whether the benefits exceed the harms, the way we are practicing now. And I think that also in terms of the American College of Physicians recommendations particularly, they assess the value of care. Does the benefit clearly justify the harms as well as the costs? And for the cost of the screening, more than just the cost of PSA testing should be considered. Keep in consideration the current practice patterns-that is, if a PSA test is ordered, there is a downstream process and consequence that could lead to a biopsy, evaluation, diagnosis, and overtreatment. The cost of that, as currently practiced makes this not a high value test. Whether we can improve on that in the future, particularly with these discussions with men and more careful selection and approach to patients is something I think we all hope we can do. Guidelines and practice should change as science changes.

Cancer Network: Thank you so much both so much for joining us today.

Dr. Carter: You’re welcome and thank you.

Dr. Wilt: Thank you.