So what are the problems with PSA screening? Well, the biggest problem I think is over-diagnosis. There are clearly people who have been diagnosed with prostate cancer that didn’t need to know, that would never had died of their disease if left untreated. What we debate is what the frequency of that phenomenon is. Whether it’s 5% or 50%, we just don’t know. The other problem with PSA-based screening is the high false-positive rate. As I showed before, only 25% of patients who have a PSA between 4-10 actually have prostate cancer. How have we improved on that? I don’t know that we have improved that much over the past 5-10 years. We clearly now know that PSA’s mean different things in different age groups. As a man gets older the size of his gland will increase, and in the population the prevalence of benign prostatic hyperplasia will increase and therefore the PSA will increase as a function of age. So a PSA of, let’s say, 4 has a different implication for a man who is 45 than it does for a man who is 75. If one takes into account these changes, one can improve the specificity of PSA screening. PSA density, which is the PSA level as a function of the size of the gland by ultrasound is useful in that people with higher PSA densities are more likely to have prostate cancer. The problem with this concept is that it requires an ultrasound and the modeling of the prostate volume is very problematic in large multi-institution studies. Therefore there is not very much consistency in terms of the numerical values of cut-offs for when people need to have a biopsy, from those when you don’t need a biopsy.

PSA velocity is an important concept in that retrospectively, if you look at the rate change of PSA over time in people who have prostate cancer, it’s much faster than those individuals who have BPH or have a completely normal prostate. The problem is that in real time in a patient who comes in with an abnormal PSA on his first visit, it’s difficult to use PSA velocity to sort out those individuals who need biopsies from those that don’t, because there is so much fluctuation in the level of the PSA over the course of time. So PSA velocity tends not to be very useful as a way of reducing the false-positive rate. Probably the most useful test is the free PSA. PSA in the blood is either complexed to alpha 1 chymotrypsin or is free floating. The proportion of free PSA in a patient with an abnormal PSA, when it increases, the likelihood of having prostate cancer increases as well. So for a slightly elevated PSA and a particularly low free PSA, this test is a useful adjunct to routine screening.

So where do we stand on screening in the United States? It is not accepted, from the standpoint of recommendation, because one has not yet documented a reduction in mortality rate. There are groups that have recommended screening, some groups that have not recommended screening, but it is generally practiced in the United States. What is recommended if one undergoes screening, and if a patient understands all the uncertainties and ramifications of screening, is yearly PSA’s and digital rectal exams beginning at the age of 50 and ending when a patient has a life expectancy under ten years. If a person is in a high risk group, that is, they have a positive family history or they are African-American, then screening should begin at the age of 40.

Conceptually staging of prostate cancer really looks like this. This is not how we really stage prostate cancer, but this is how we should think about staging prostate cancer and this is where we ultimately want to go. There are those patients who have prostate cancer that don’t need to be treated. Either because their disease is so indolent that it is not progressing or has a very low likelihood of metastasizing, or their life expectancy is limited. There are those individuals that should be cured in that they have a more aggressive phenotype or they have a longer life expectancy and they still have organ-confined and curable prostate cancer. This is the most important subgroup. The last subgroup are those individuals that we would like to cure but cannot be cured because they have microscopic metastatic disease. We are improving our ability to separate these entities but we are still not quite there yet. I’ll go into that in a little bit of detail.

Now this is a very important study that Peter Albertson and his colleagues published a year ago in JAMA, looking at the natural history of untreated prostate cancer. In this study there were 3,000 men who were registered within the Connecticut cancer registry who were diagnosed with prostate cancer who, either because they chose not to get treated or their physicians didn’t recommend treatment, were ultimately not treated and followed without treatment for 15 years or longer. And the question being asked in this particular study is, “What is the likelihood of dying of the disease and what are the predictors of dying of the disease?” Common sense would lead you to believe that clearly age is an important factor; the older you are the less likely you are going to die of the disease. The other important factor was the grade of the original tumor. So we learned something about the predictors, we also learned something about the natural history. A very common scenario that we see in our clinic nowadays is a 70-year-old man with a Gleason 3+3 cancer. The likelihood of that individual dying of prostate cancer by 15 years if left untreated is only about 25%. Obviously a younger man has a higher likelihood of dying of the disease and a more aggressive tumor, a higher Gleason score, higher as well. But this is an interesting paper that you should all take a look at to understand what untreated prostate cancer looks like.

Now an important part of how we deal with patients is determining their likelihood of cure. This is something that we actually know a fair amount about right now but it isn’t always practiced in the clinic. These are the factors which determine the likelihood of having organ-confined prostate cancer and likelihood of cure: serum PSA, the lower the level the more likely it is organ-confined, grade, clinical stage, and the number of biopsies that contain prostate cancer. Now just as a background, the most common grading system that we use in the United States right now is the Gleason grading system, which is not a cytological grading system but a histological grading system in that it only takes into account the glandular patterns. In this scheme the arrangements are scaled on a scale of 1-5 where the primary pathology is first, secondary pathology is second, and the Gleason score or sum is the addition of these two subsets. The problem with this – although it’s highly predictive of the likelihood of having metastatic disease and overall behavior – is that most of the tumors that we now see in the clinic are Gleason 6 and 7. Probably 70-80% of the tumors fit into those categories. So there is a narrow range and there are very few tumors now that are a 2 or 3 or 4 and only 10% that are a 9 or 10.