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New Treatments for Prostate Cancer

This year there will be almost 180,000 cases of prostate cancer diagnosed, and 37,000 deaths from the disease. There has been a very interesting pattern of incidence of prostate cancer in the United States over the past 30 years, which is illustrated by this slide, in the African-American population which is the top curve and in the Caucasian population in the United States. As you can see, over the past 20-30 years there was a steady but slow rise in the incidence of prostate cancer in these two populations, beginning in the later 1980ís, 1990ís, a rapid increase in incidence rates. This we attribute to several factors; increasing awareness, greater ease of doing biopsies, the development of the biopsy gun.

Now this is how we think of prostate cancer. Prostate cancer is the disease that arises in the epithelium of the prostate. The first recognizable pathological entity is known as prostatic intraepithelial neoplasia, which is the prostatic equivalent of carcinoma in situ in breast cancer; which in contrast to bladder cancer, is not a nasty entity but a disease that may coexist with invasive prostate cancer or may ultimately become prostate cancer.

Ultimately prostate cancer will metastasize and generally it consists of a heterogenous group of cells which are both androgen sensitive and androgen insensitive. So the strategy in patients with advanced disease is to remove androgen and remove the androgen sensitive population, reduce tumor bulk. Patients will almost always go into a remission but ultimately what emerges is a pure population of androgen insensitive cells.

Whatís the cause of prostate cancer? Well, we really donít know. We do have some associations, some important risk factors. Obviously male gender is the most important one. Aging is important as well. As you can see, this is just one population. This is in the inner-city Detroit population in African-Americans and in Caucasians. The increasing incidence of prostate cancer as a function of age. Nowadays about 10-15% of patients will be diagnosed under the age of 50. There has been a tendency for younger patients to be diagnosed, obviously because of the use of PSA. Probably more than any other malignancy there is a relationship, a strong relationship, with age. Race and ethnic background is important as well.

Growth factors are important as well. The most important of which so far has been insulin-like growth factor 1. There is a relationship between the level of IGF1 and likelihood of developing subsequent prostate cancer. Genetic factors, much like other epithelial adult tumors, are important as well. This is best described within the context of the Health Professional Follow-up Study.

Now why is genetics important? In this study from the Cleveland Clinic of 1,000 men who came in with prostate cancer that were treated for their prostate cancer, those individuals who gave a positive family history did poorer with treatment than did patients with no family history of prostate cancer. Perhaps there are some genes involved in familial prostate cancer that give rise to a more aggressive phenotype. That is the hypothesis that is suggested by this data. Now genetics is a complex thing. Part of the story here is familial prostate cancer, much like familial breast cancer, familial colon cancer. Familial prostate cancer probably represents 5-10%.

Now if we know something about the epidemiology of prostate cancer, maybe we can get some hypotheses regarding the prevention of this disease. Suffice it to say that there have been no prospective randomized studies with intervention.

Now letís move on to some more clinically relevant subjects, particularly screening for prostate cancer. So let me summarize 10-15 years of work thatís been done in screening in one slide. I think this summarizes much of what we know right now. In the old days the screening test that we had for prostate cancer was the digital rectal exam. A lot of inter-observer variability. When one detects an abnormality by digital rectal exam, more often than not is the tumor outside of the prostate. When you combine the digital rectal exam with the prostate specific antigen you can detect three times as many cancers as one did by the digital rectal exam alone. From the Physicians Health Study we learned that when one uses PSA.

Now the big question with screening for prostate cancer is whether the strategy of PSA-based screening will reduce the mortality from the disease. There is one screening study that was presented at ASCO two years ago that was so methodologically flawed that we donít use it as evidence for screening, but it did show some benefit for screening. Some people have looked at the slight reduction in mortality of this disease in the United States.

What we have noticed clinically in the United States - this is once again from the SERE cancer registry in the United States - these are the rates of stages C and D prostate cancer at presentation in Caucasian and African-Americans.

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 didnít 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 itís 5% or 50%, we just donít 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.

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, itís 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, itís difficult to use PSA velocity to sort out those individuals who need biopsies from those that donít, because there is so much fluctuation in the level of the PSA over the course of time.

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.

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 donít 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.

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 didnít recommend treatment, were ultimately not treated and followed without treatment for 15 years or longer.

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 isnít 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.