EXPECTANT MANAGEMENT OR ACTIVE SURVEILLANCE

The Brady Urological Institute has achieved world renown for discoveries that led to improvements in the surgical treatment of prostate cancer. However, not every man will benefit from treatment since some cancers will never progress to a harmful state. Researchers at the Brady Urological Institute have a commitment to learn how to identify those men who can safely forego treatment -instead undergoing careful follow up for any evidence of progression of their disease. An expectant management program at the Brady Urological Institute under the direction of Dr. Ballentine Carter and Dr. Jonathan Epstein is currently following more than 250 men who are thought to have tumors that can be safely managed without immediate treatment.

Prostate cancer is the most prevalent male cancer, but the majority of men with the disease do not die of prostate cancer. Recent studies suggest that 30-50 percent of men over the age of 60 years diagnosed with prostate cancer today by PSA screening would never have known they had prostate cancer during their life if a prostate biopsy had not been performed. For these men, the news that they have prostate cancer will not be beneficial and their treatment will not add years to life. This does not mean that prostate cancer does not kill men, but rather that some older males have a slowly progressive form of the disease that will not threaten them during the remaining years of their life. The key is to be able to identify those older men who for now can safely forego treatment.

Which patients are the best candidates for no immediate treatment or expectant management?

There are 3 groups of men with prostate cancer that could be managed expectantly:

1. those too old or too ill to benefit from treatment;
   
2. those with cancer that is too far advanced to cure who want to maintain their quality of life by foregoing treatment until there is radiographic evidence of distant disease;
   
3. those with small volume prostate cancers discovered with PSA screening.

We are currently evaluating this latter group in an expectant management study that identifies older men with PSA detected prostate cancers that are thought to be small volume. It is known that more than 25 percent of prostate cancers detected with PSA testing (and normal digital rectal examination) are very small cancers that are not poorly differentiated. These tumors may not cause harm -especially in older men who have less time for the tumor to progress.

Eligible men should meet the following criteria:

• older age -usually men in their 60’s or those with other health problems
• cancer can not be felt on digital rectal examination (referred to as stage T1c)
• PSA appropriate for prostate size meaning that the PSA density (PSA divided by ultrasound determined prostate volume) is 0.1 or less
• combined Gleason grade or score is 6 or less and no more than 2 biopsy cores contain cancer and
• cores containing cancer should not have more than 50 percent involvement with cancer
  

Those men who are interested in expectant management should contact Dr. Ballentine Carter at 410-955-0351.

What does expectant management mean?

In the past, expectant management meant no treatment until the development of metastatic disease, at which time androgen ablation (hormonal) therapy was initiated. However, for those men who are thought to have small PSA-detected prostate cancers, and who choose expectant management as an alternative to immediate treatment, it makes sense to monitor the situation closely and intervene -if necessary- at a time when cure is still possible. We refer to this as expectant management with curative intent. This means that men undergo periodic evaluations including PSA tests, digital rectal examinations, and prostate biopsies. If there is evidence that the cancer is progressing, treatment is recommended with the intention of curing the disease.

Is it possible to accurately identify those men who have small PSA detected cancers that are less likely to progress without treatment?

The answer depends upon your definition of accurate. Dr. Jonathan Epstein, , an expert in prostate pathology at Johns Hopkins Hospital, has shown in two separate studies (one retrospective and one prospective) that cancers less than 0.5 cc (smaller than an eraser tip) can be identified correctly about 75 percent of the time using PSA and information from the prostate biopsy. Dr. Epstein's criteria provide a method for helping men choose between expectant management and immediate treatment.

The Epstein Criteria:

• If the PSA density (PSA divided by prostate volume on ultrasound) is lower than 0.1 and there are no adverse findings on needle biopsy (Gleason score 7 or greater, or more than two needle biopsies containing prostate cancer, or more than 50 percent involvement of any core with cancer), then there is a 70 to 80 percent chance that the prostate cancer is small volume (less than 0.5 cc).
  
• If the PSA density is 0.1 or more, or if there are any adverse findings on needle biopsy, then there is a 70 to 80 percent chance that the tumor is larger than 0.5 cc.

Are there any other tests that are useful for predicting which prostate cancers need to be treated?

Investigators at the Brady Urological Institute and the Baltimore Longitudinal Study of Aging discovered that free PSA is predictive of the aggressiveness of prostate cancers. Using frozen serum samples to measure PSA and free PSA long before the diagnosis of cancer was made, it was found that the percentage of free PSA (PSA in the blood not bound to proteins) distinguished between aggressive (high grade) cancer and non-aggressive cancer 10 years before the cancers were diagnosed. The percentage of free PSA in the blood fell as the tumors progressed toward the date of diagnosis. A percent free PSA of 15 or lower was predictive of the diagnosis of aggressive prostate cancer 10 years later.

Dr. Epstein demonstrated in another study that a percent free PSA higher than 15 was predictive of the presence of small volume disease in men with PSA detected prostate cancer. And in a study from Washington University in St. Louis, investigators found that a percent free PSA lower than 15 was predictive of more extensive, higher grade disease at the time of radical prostatectomy. So, three separate studies with very different designs have concluded that percent free PSA is predictive of the biology of the tumor. Based on these data, we are less enthusiastic about expectant management in men who have a percentage of free PSA that is consistently less than 10-15.

How does a man with a PSA-detected prostate cancer that is thought to be small volume make a choice between expectant management and treatment?

At the Brady Urological Institute we do not encourage healthy men in their 50’s to strongly consider expectant management because of their longer life expectancy, and the uncertainty of whether a tumor will progress during the remaining years of life. For older men with PSA-detected prostate cancers that are thought to be small volume, expectant management is one of the options that can be considered. A man should weigh the potential loss of quality of life with treatment (radiation or surgery) against the possibility that the window of opportunity for cure will disappear without treatment. In the era before PSA testing became widespread, men over age 65 with localized prostate cancer that was not poorly differentiated, had a probability of death from prostate cancer in the range of 25 percent over 15 years without treatment. Now, with PSA testing, prostate cancers are detected on average 10 years earlier than in the pre-PSA era. Since tumors are being detected earlier than ever before, one would anticipate that the probability of death from prostate cancer for men over age 65 years with a PSA detected cancer (not poorly differentiated) would be much lower than 25 percent over 15 years with expectant management. This, however, currently remains unproven.

What does a man have to loose with expectant management of a PSA-detected cancer?

The major concern is that while expectant management is taking place, the tumor will progress beyond the prostate to the point where cure is no longer possible. At the Brady Urological Institute, we are following more than 250 men (average age 67) with PSA-detected prostate cancers who have chosen expectant management because there is evidence based on the Epstein criteria that small volume disease is present. Although we do not have long term follow-up (more than 10 years) to make definitive statements, about 30 percent of men with follow-up have had adverse findings on a repeat prostate biopsy one year or more after the initial prostate biopsy diagnosed the cancer. At this point, treatment was recommended because of the biopsy findings showing more cancer (more than 2 cores with cancer, and/or more than 50% involvement of any core with cancer, and/or high grade disease). Of the men who have undergone surgery to treat their prostate cancer at the time the follow-up biopsy showed adverse findings, the proportion with curable disease appears to be similar to those men who would have qualified for the program but chose to undergo surgery immediately instead of expectant management. Thus, it would appear that when men are carefully selected for expectant management, the window of opportunity for cure is unlikely to close with monitoring.

There is an important caveat. It is most likely -given the slow progression of prostate cancer - that the men found to have more extensive disease at follow-up prostate biopsy did not have small volume disease to begin with. In other words, the tumor was initially under-sampled with needle biopsy. So, men who choose expectant management should realize the uncertainty involved in predicting the presence of small volume disease and be willing to live with this uncertainty. To minimize the chances of under-sampling, we now recommend that men undergo a confirmation biopsy (see below) prior to entering this program.

If a man decides on expectant management, what recommendations are made for follow-up of the cancer?

Because of the uncertainty associated with prostate biopsy and the prediction of small volume cancer, we recommend that any man interested in expectant management undergo a repeat prostate biopsy (12 to 14 core confirmation biopsy) with wide area sampling to minimize the chance that more extensive -or higher grade- disease was missed on the initial biopsy. This is done prior to making a decision regarding management. If the repeat biopsy does not turn up more extensive disease, and the individual is comfortable with expectant management, we recommend a PSA and digital rectal examination at six-month intervals and a yearly prostate biopsy (surveillance biopsy) to monitor the progress of the disease.

Our current data show that in men who undergo confirmation biopsies, 39% will show no cancer present, 31% show cancer with characteristics favorable for the expectant management program, and 30% show more extensive cancer or higher grade cancer for which we would recommend treatment. Thus, 2 out of 3 men who undergo confirmation biopsies will have a biopsy result that would qualify them for the expectant management program.

Among those men who have been followed with annual surveillance biopsies after the confirmation biopsy and entering the program, we have seen the following results. Progression (higher grade or more extensive cancer on biopsy) eventually occurred in 12% of men whose first surveillance biopsy showed no cancer and 5% of men whose first and second surveillance biopsy showed no cancer. By comparison, progression eventually occurred in 29% of men whose first surveillance biopsy showed cancer without adverse findings, and in 22% of men whose first and second surveillance biopsy showed cancer without adverse findings. Therefore, the finding of no cancer on surveillance biopsies is predictive of the absence of disease progression later on.

Why is a yearly prostate biopsy necessary?

We have found in following men with PSA-detected prostate cancers, that changes in PSA are not reflective of who will and will not be found to have more extensive disease on follow-up biopsies. This is consistent with other published data demonstrating that men can have progression of prostate cancer without significant rises in PSA. Thus, one should not depend on PSA to sound the alarm that treatment is now necessary when following men who have chosen expectant management.

If a man chooses expectant management, what dietary changes should he make?

Most men ask what they should be doing in terms of dietary changes to help prevent progression of the disease. This is an area of intense interest now but it's one that is clouded by the fact that dietary supplements are a billion dollar industry in the U.S. This often makes it hard for consumers to distinguish between science and marketing. There is a very nice review on the topic of nutrition and cancer in CA, A Cancer Journal for Clinicians, published for the American Cancer Society. The review can be found on their web sitehttp://www.ca-journal.org

The bottom line is that there is an association between intake of animal fat and the incidence of prostate cancer, and that fruits and vegetables can reduce the risk of many cancers. Thus, a diet that is mostly made up of food from plant sources (fruits, vegetables, soy), and that limits the intake of high fat foods makes sense for now. As for vitamin supplementation, there is preliminary evidence that vitamin E and selenium may be protective with regard to prostate cancer. However, the trials that suggest this were not designed to address a relationship between prostate cancer, vitamin E, and selenium, so strong recommendations for supplementation of vitamin E and selenium cannot be made based on the available data. Lycopene, an antioxidant found in high concentration in tomatoes and grapefruit, is thought to be protective against prostate cancer development and it makes sense to consume foods high in lycopene which are part of a healthy diet.